Neuronal correlates and serotonergic modulation of behavioural inhibition and reward in healthy and antisocial individuals

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Abstract

Individuals with antisocial personality disorder (ASPD) are impulsive and show impairment in reinforcement processing. There is increasing evidence for a neurobiological basis of psychopathy, which shares some of the characteristics of ASPD, but research on the neuronal correlates of neuropsychological processes in ASPD remains limited. Furthermore, no research has examined the effects of serotonergic manipulation on brain activations in antisocial groups. In this study, 25 male participants with ASPD (mean age 42.1) and 32 male control participants (mean age 30.5; 25 participants providing usable scans) were randomly allocated to receive the 5-HT2C-agonist mCPP or placebo. Participants were scanned using functional magnetic resonance imaging (fMRI) during a behavioural inhibition (Go/NoGo) and a reward task. In comparison to healthy controls the ASPD group showed reduced task related activations in the dorsolateral prefrontal cortex (DLPFC) but increased signal in the pre/subgenual anterior cingulate cortex (ACC) in the Go/No-Go task and increased activation in OFC in the reward task. mCPP modulated brain responses in both tasks in the whole group. Interactions between group and drug occured in bilateral OFC, caudate and ventral pallidum during the reward task but no significant interactions were found in the Go/No-Go task. This suggests that ASPD involves altered serotonin modulation of reward, but not motor inhibition pathways. These findings suggest that ASPD involves altered DLPFC, ACC and OFC function. Altered serotonergic modulation of reward pathways seen in the ASPD group raises the possibility that targeting serotonin systems may be therapeutic.

Introduction

Antisocial personality disorder (ASPD) is characterised by a disregard for and violation of rights of others (APA, 1994) and is associated with increased rates of aggressive and criminal behaviour. There is increasing evidence for a neurobiological basis of ASPD, including genetic liability, aberrant serotonergic function, neuropsychological deficits and structural and functional brain abnormalities (reviewed in Pridmore et al. (2005)). Individuals with ASPD display behavioural symptoms, such as impulsivity, as well as affective impairment. Previous neuroimaging research has mainly focused on the affective component of the disorder; little work has been conducted investigating the neuronal correlates of impulsive responding in this group.

In healthy individuals neuronal correlates of behavioural inhibition, one aspect of impulsivity, include anterior cingulate (ACC), dorsolateral prefrontal cortex (DLPFC) and orbitofrontal cortex (OFC) (reviewed in Elliott (2005)). In antisocial groups abnormal brain activations during tasks requiring restraint of motor responding (Go/No-Go tasks) have been described (Völlm et al., 2004). Functional neuroimaging studies using reward tasks in healthy control groups (reviewed in O’Doherty (2004)) have implicated a number of brain regions mediating the behavioural and motivational effects of reward, including ventral striatum, dopaminergic midbrain, amygdala and orbitofrontal cortex. Amygdala, striatum and midbrain appear to be involved in the experience of reward while OFC is thought to mediate the integration of reward and punishment stimuli to inform future behaviour. Behavioural (Dolan and Park, 2002) and imaging (Völlm et al., 2007) studies in personality disordered groups have led to the proposal that deficits observed in behavioural choice involving reward and punishment may be related to prefrontal cortex dysfunction in Cluster B personality disordered patients.

An inverse relationship between impulsivity and 5-HT function has been demonstrated across a broad range of population samples (Dolan et al., 2001). 5-HT modulation has also been associated with alterations in behavioural choice following reward and punishment (Cools et al., 2005). Recently, neuroimaging research has investigated how 5-HT might exert its effect on these neuropsychological processes. In healthy individuals several studies have shown enhanced brain activations in prefrontal, particularly orbitofrontal, cortex during behavioural inhibition after administration of a range of different serontonergic drugs (Anderson et al., 2002, Del Ben et al., 2005, Völlm et al., 2006). Enhanced parietal cortex activations were identified during reward processing (Völlm et al., 2006).

In this study we used functional magnetic resonance imaging (fMRI) to identify brain areas associated with behavioural inhibition and reward in healthy and ASPD individuals and differences in activations between the two groups. We further investigated the effect of a serontonergic manipulation with the 5-HT2C-agonist m-chlorophenylpiperazine (mCPP) on these activations. Due to the deficient baseline 5-HT function in ASPD individuals, we hypothesised that a drug enhancing postsynaptic 5-HT function would have a larger effect on task related signal change in the ASPD group compared to the healthy control group.

Section snippets

Participants

Male ASPD participants were recruited from a variety of sources including a high security and a private sector medium security forensic psychiatric hospital and an open prison, all located in the North-West of England. Additional individuals were recruited via probation and from the general public using newspaper advertisements. Male healthy control participants were recruited from university staff (particularly non-academic staff) and the student population as well as from the general public.

Sociodemographic and behavioural data

Control participants were significantly younger than those with ASPD (mean controls 30.5, range 18–55; mean ASPD 42.1, range 29–56; P < 0.001). Individuals with ASPD and healthy control participants differed in years of education (12.3 vs. 16.4: P < 0.001). However, IQ scores were not significantly different between the two groups (mean controls 103.9, range 89–130; mean ASPD 99.4, range 89–113; P = 0.077).

ASPD participants had higher total BIS scores compared to control individuals which just missed

Discussion

In this study we examined two neuropsychological processes proposed to be impaired in antisocial individuals: impulsivity and reward processing. We investigated task performance on a Go/No-Go and a reward task and used fMRI to identify brain activations associated with performing these tasks in antisocial personality disordered individuals and in a healthy control group. We further explored whether a serontonergic drug challenge (mCPP) modulated task related neuronal activations. Our results

Conclusions

In conclusion, in this study we demonstrated reduced task related brain activations in prefrontal and parietal regions during performance of a behavioural inhibition task as well as increased engagement of parts of the reward circuit during a reward task in a group of individuals with ASPD. This may reflect deficits in executive function and a possible attentional component to impulsivity in ASPD. We also found evidence that the restraint condition engaged pre/subgenual cortex and other emotion

Role of funding source

Funding for this study was provided by the Medical Research Council; the MRC had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication.

Contributors

B.V., P.R., R.E., I.A., S.W., M.D. and B.D. were involved in the design of the study; B.V., P.R., R.E., I.A., S.W., M.D. and B.D. wrote the protocol. B.V. and P.R. collected the data; B.V. and P.R. managed data collection and databases; B.V., P.R., S.M. and R.R. analysed the data; B.V. wrote the first draft of the manuscript. All authors contributed to and have approved the final manuscript.

Conflict of interest statement

None declared.

Acknowledgements

We acknowledge the support of the Manchester Clinical Research Facility.

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