Inhibitory deficits in the dorsolateral prefrontal cortex in psychopathic offenders

Inhibitory deficits in the dorsolateral prefrontal cortex in psychopathic offenders

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Available online at www.sciencedirect.com

Journal homepage: www.elsevier.com/locate/cortex

Research report

Inhibitory deficits in the dorsolateral prefrontal cortex in psychopathic offenders Sylco S. Hoppenbrouwers a, Danilo R. De Jesus b, Tania Stirpe c, Paul B. Fitzgerald d, Aristotle N. Voineskos b, Dennis J.L.G. Schutter a,1 and Zafiris J. Daskalakis b,*,1 a

Department of Experimental Psychology, Helmholtz Institute, Utrecht University, Utrecht, The Netherlands Centre for Addiction and Mental Health, University of Toronto, Toronto, Ontario, Canada c Correctional Service of Canada, Central Ontario District (Parole), Psychology Department, Toronto, Ontario, Canada d Monash Alfred Psychiatry Research Centre, The Alfred and Monash University School of Psychology and Psychiatry, Victoria, Australia b

article info

abstract

Article history:

Often typified as cunning social predators, psychopathic offenders show a persistent

Received 13 December 2011

pattern of impulsive and reckless behavior, the pathophysiology of which has been related

Reviewed 5 April 2012

to dysfunction in the dorsolateral prefrontal cortex (DLPFC). That is, the DLPFC is important

Revised 13 April 2012

for the regulatory control of impulses and emotion as well as working memory and

Accepted 10 June 2012

psychopathic offenders show impairments in all three dimensions. In the present study,

Action editor Angela Sirigu

we used combined transcranial magnetic stimulation and electroencephalography to

Published online xxx

compare the physiology of the DLPFC in 13 psychopathic offenders and 15 healthy subjects vis a` vis excitability and inhibition. In addition, working memory performance was

Keywords:

measured through the letterenumber sequencing test. Results showed that compared to

Psychopathy

healthy subjects, psychopathic offenders had inhibition not excitability deficits in the

Transcranial magnetic stimulation

DLPFC that was accompanied by deficits in working memory performance. In healthy

Electroencephalography

controls and psychopathic offenders working memory performance correlated with the

Cortical inhibition

extent of inhibition over the DLPFC. Taken together, these findings suggest that psycho-

Working memory

pathic offenders suffer from dysfunctional inhibitory neurotransmission in the DLPFC and

Behavioral disinhibition

impaired working memory which may account for the behavioral impairments associated with this disorder. ª 2012 Elsevier Srl. All rights reserved.

1.

Introduction

Psychopaths are notorious for their callous unemotional personality style and Machiavellianistic use of others. Likely to engage in criminal and aggressive behavior they burden society with enormous costs in addition to inflicting severe

emotional harm on their victims (Patrick, 2006). Although psychopathic offenders are capable of executing well-planned crimes (Herve´ et al., 2004), they typically act impulsively and do not deliberate the consequences of their actions, neither for themselves nor for others. As reflected in Hare’s Psychopathy Checklist-revised second edition (PCL-R:2) (Hare,

* Corresponding author. Schizophrenia Program, Associate Professor of Psychiatry, Centre for Addiction and Mental Health, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada. E-mail address: [email protected] (Z.J. Daskalakis). 1 These authors contributed equally to this work. 0010-9452/$ e see front matter ª 2012 Elsevier Srl. All rights reserved. http://dx.doi.org/10.1016/j.cortex.2012.06.003

Please cite this article in press as: Hoppenbrouwers SS, et al., Inhibitory deficits in the dorsolateral prefrontal cortex in psychopathic offenders, Cortex (2012), http://dx.doi.org/10.1016/j.cortex.2012.06.003

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2003) psychopaths display poor behavioral controls, are impulsive and irresponsible and lack the ability to formulate realistic long-term goals (Hare, 2003). In line, Patrick et al. (2009) proposed a tripartite conceptualization of psychopathy in which meanness, boldness and disinhibition are emphasized. According to this conceptualization, disinhibition refers to “impulse control problems, lack of planfulness and foresight, impaired regulation of affect and urges, insistence on immediate gratification and deficient behavioral restraint” (Patrick et al., 2009). Whereas psychopaths may describe this behavior as ‘living in the moment’ (Babiak and Hare, 2006), in reality these clinical observations point toward cognitive dysfunction, i.e., the incapacity to inhibit impulses and regulate emotion and behavior. Indeed, psychopathic offenders present with higher levels of impulsive-reactive anger (Blair, 2010), response perseverance (Newman et al., 1987), attention deficits (Baskin-Sommers et al., 2011; Newman et al., 2010) and are generally unresponsive to inhibitory information (e.g., potential punishment or negative outcomes) (Zeier et al., 2009). Therefore, psychopathic offenders are thought to exhibit deficits in higher-order cognitive processes (Gao and Raine, 2010; Yang and Raine, 2009) making them vulnerable to a disinhibited antisocial lifestyle. The dorsolateral prefrontal cortex (DLPFC) is important in the regulation of emotion and behavior and is dysfunctional in psychopathy (Rilling et al., 2007; Dolan and Park, 2002), particularly the left DLPFC (Yang and Raine, 2009). Damage to the left DLPFC generates impairments in attention, cognitive flexibility and impulse control that are involved in regulatory control (Yang and Raine, 2009). The authors subsequently suggest that decreased functioning of the left DLPFC in psychopathic offenders can result in antisocial behavior including impulsivity and behavioral disinhibition (Yang and Raine, 2009). The DLPFC is also involved in higher-order cognitive functions such as working memory (Daskalakis et al., 2008b; Smith et al., 1998; Goldman-Rakic, 1995). Working memory involves the online storage and manipulation of information (Barr et al., 2010; Baddeley, 1986) while resisting interference (Kane and Engle, 2003; Kane et al., 2001). Working memory is important for impulse control (Arnsten, 2009), goal-directed behavior (Lepsien et al., 2011) and response inhibition (Chambers et al., 2009). Lower working memory capacity results in less control of emotional responding (Schmeichel et al., 2008) and reduced emotional self-regulation after negative feedback (Schmeichel and Demaree, 2010). Working memory deficits are also correlated with characteristics of secondary psychopathy, i.e., the impulsive antisocial lifestyle (Sadeh and Verona, 2008). Deficits in working memory may therefore result in the impulsive disinhibited behavior and poor emotion regulation observed in psychopathic offenders. At a neurophysiological level, working memory involves the recruitment of inhibitory interneurons in the DLPFC (Goldman-Rakic, 1995). The phenomenon of cortical inhibition (CI) is defined as the neurophysiological suppression of cortical output neurons by inhibitory interneurons that use g-aminobutyric acid (GABA) as their primary neurotransmitter (Iversen et al., 1971; Fitzgerald et al., 2009). This form of inhibitory neurotransmission can be quantified with paired pulse transcranial magnetic stimulation (TMS). That is, TMS

generates magnetic fields that travel through the cranium to both inhibitory and excitatory interneurons that can, in turn, be measured. Traditionally confined to measurement from motor areas, the combination of TMS with electroencephalography (EEG) has enabled researchers to study inhibitory and excitatory processes from non-motor cortical areas such as the DLPFC (Farzan et al., 2009; Daskalakis et al., 2008b). The advantage of TMS combined with EEG is that it measures real time physiological processes and networks in the brain. GABAergic inhibitory neurotransmission in the DLPFC has been reported to correlate positively with working memory performance (Daskalakis et al., 2008b) and suggests a strong interplay between inhibition in the DLPFC and working memory performance, both of which are important in the control of behavior. The aim of this study was to assess inhibition and excitability directly from the left DLPFC in psychopathic offenders compared to healthy subjects whilst measuring working memory performance. We hypothesized that psychopathic offenders would demonstrate poorer working memory performance and decreased CI over the DLPFC but not over the motor cortex. In addition, we anticipated that the previously observed relationship between working memory and CI over the DLPFC (Daskalakis et al., 2008b) would be replicated.

2.

Methods and materials

2.1.

Participants

Thirteen right-handed male psychopathic offenders (age in years: mean  standard deviation (SD), 34.2  9.2; age range 22e55) and fifteen right-handed (Oldfield, 1971) age-matched healthy male subjects (age in years: mean  SD, 34.0  9.9; age range 22e51) were enrolled in the study. Psychopathic offenders were recruited through posters displayed in halfway houses in the Greater Toronto Area and through the Law and Mental Health Program at the Centre for Addiction and Mental Health (CAMH). Halfway houses are residential facilities for men on conditional release to the community. Their function is to assist in gradual community reintegration while providing supervision. Thirty-eight violent offenders were interviewed of which twenty-one offenders met criteria for inclusion, although 6 re-offended before they could be included in the study. The thirteen psychopathic offenders that were included scored 25 or higher (mean  SD, 28.8  3.0) on the PCL-R:2 (Hare, 2003). Offenders were asked to sign a Release of Information after which a review of case notes and psychological assessments was carried out to retrieve the PCL-R score and to exclude co-morbid psychiatric or neurological disorders. Exclusion criteria included age under 18 or over 65, schizophrenia, schizophreniform/psychotic disorders, bipolar disorder, affective or anxiety disorders or any comorbid personality disorders. Exclusion criteria for all subjects included substance abuse or dependence in the last 6 months determined through the Diagnostic Statistical Manual-IV-TR (DSM-IV-TR). However, 87% of the included psychopaths reported a history of drug use and had previously met criteria for substance use disorder. Drug screening at the halfway houses indicated none of the psychopathic offenders

Please cite this article in press as: Hoppenbrouwers SS, et al., Inhibitory deficits in the dorsolateral prefrontal cortex in psychopathic offenders, Cortex (2012), http://dx.doi.org/10.1016/j.cortex.2012.06.003

c o r t e x x x x ( 2 0 1 2 ) 1 e9

were abusing drugs around the time of testing. Psychopaths had previously been administered the Shipley Institute of Living Scale and all scored in the average range. The Shipley Institute of Living Scale screens for organic brain damage and has a high correlation (r ¼ .85) with the full scale Wechsler Adult Intelligence Scale (WAIS)-R (Weiss and Schell, 1991). Healthy controls were recruited through advertisement. Six healthy volunteers were unemployed at the time of testing. Psychopathology in the control group was ruled out through a standard clinical interview and the Personality Assessment Screener (PAS) (Psychological Assessment Resources, Inc.) The PAS is a self-administered, objective inventory of adult personality and psychopathology (e.g., personality disorder, depression, somatic disorders, anxiety, anxiety-related disorders, suicidal ideation and schizophrenia). Specifically, the PAS measures manifestations of clinical syndromes, providing information to assist diagnosis, treatment, and screening for all psychopathology corresponding to DSM-IV categories (Morey, 1991, 1996). All participants were free of contraindications to TMS confirmed by a standard interview (Keel et al., 2001). This study was approved by the Research Ethics Board. Written informed consent was obtained for all participants. All subjects were paid for participation.

2.2.

Procedure

TMS pulses were administered with a 7-cm figure-of-eight coil connected to a Bistim module powered by two Magstim 200 stimulators (Magstim Company Ltd., UK). Motor evoked potentials (MEPs) were recorded and analyzed with Signal (Cambridge Electronics Design, UK). TMS pulses were administered to the left motor cortex and left DLPFC. Motor threshold (MT) was defined as the minimum stimulus intensity that elicits an MEP of 50 mV in 5 out of 10 trials (Rossini et al., 1994) and was measured with and without the EEG cap. Given the unpredictable nature of this population and the high likelihood of reoffending, we decided not to conduct a magnetic resonance imaging (MRI)-based localization of the DLPFC prior to the TMS session, in order to improve the chances that subjects would complete the study. Stimulation of the left DLPFC was therefore done through a previously reported method that suggests that stimulation over F5 is the optimal location for targeting the DLPFC when MRI-based co-registration is not available (Rusjan et al., 2010). The handle of the coil pointed backward, perpendicularly to the presumed direction of the central sulcus, approximately 45 to the mid-sagittal line.

2.3.

Measurement of CI

CI was indexed through measurement of long interval intracortical inhibition (LICI) which involves a suprathreshold conditioning stimulus (CS) and a suprathreshold test stimulus (TS) separated by a long interstimulus interval (ISI), e.g., 100 msec (Valls-Sole et al., 1992). At an ISI of 100 msec LICI has been shown to be optimal (Sanger et al., 2001), that is, inhibition is strongest at this ISI. Stimulus intensity was adjusted to generate MEPs of 1 mV peak-to-peak which was on average 53% of maximum machine output for the control group and 47% of maximum machine output for the psychopathy group. Although it has been shown that CI measured through EEG

3

strongly relates to CI measured through MEPs, these measures of CI are not identical and therefore, as an extra check, we also recorded MEPs. Per condition (TS alone or CSeTS) one hundred trials were applied, i.e., each block consisted of only test stimuli or both conditioning and test stimuli and these separate blocks were compared against each other to calculate CI. Pulses were administered at a frequency of .2 Hz which prevents habituation to repeated stimulation (Kujirai et al., 1993; Nakamura et al., 1997; Sanger et al., 2001).

2.4.

EEG

EEG was recorded with a 64 channel Synamps2 DC-coupled EEG system (Compumedics). Four electrodes were used to record eye movement induced artifact, two on the outer side of the eyes and one above and one below the left eye. The reference electrode was placed on the vertex just posterior to the CZ electrode. EEG signals were recorded DC at a sampling rate of 20 kHZ and low-pass filtered at 100 Hz. Offline processing was done with Neuroscan (Compumedics). Data was first downsampled to 1 kHZ and cut into segments that included 1000 msec pre-TS and 1000 msec post-TS activity. Segments were baseline-corrected until 110 msec pre-TS to ensure a TMS-free baseline. Post-TS intervals (25e1000 msec) that were artifact-free were extracted and digitally filtered using a zero-phase shift 1e100 Hz bandpass filter (48 dB/Oct). Hereafter, epochs were visually inspected to exclude movement, eye blink or TMS artifacts. The remaining epochs were averaged and eye blink corrected according to previously described methods (Croft et al., 2005; Farzan et al., 2010; Daskalakis et al., 2008a). Finally, the average eye blink-corrected EEG waveforms were imported into MATLAB (The Mathworks Inc., Natick, MA) where further analyses were carried out with the EEGLAB toolbox (Delorme and Makeig, 2004).

2.5.

Measures of LICI

MEPs were measured from the abductor pollicis brevis (APB) muscle by two disposable disc electrodes in a tendon-belly arrangement. LICI was expressed through [1  (MEPconditioned/ MEPunconditioned)  100] in which 0% expresses no inhibition and 100% expresses complete inhibition (Daskalakis et al., 2002, 2004, 2008b). For LICI measured from EEG the following formula was used: ½1ðarea under rectified curve ðconditionedÞ= area under rectified curve ðunconditionedÞÞ  100: The eye blink-corrected average waveforms were bandpass filtered (1e50 Hz) and the area under the curve for the conditioned and unconditioned waveforms was generated. The area under the curve was measured between 50 and 150 msec post stimulus for both the CS and TS. The first time (i.e., 50 msec post stimulus) was chosen as it represents the earliest artifactfree data that can be recorded post stimulus, and the second time (i.e., 150 msec post stimulus) was chosen as it represents the duration of GABAB receptor-mediated inhibitory postsynaptic potentials (IPSPs) (Deisz, 1999) (i.e., 250 msec) elicited by the CS (Sanger et al., 2001). For measurement of cortical evoked potentials (CEPs) over the motor cortex the C3 electrode

Please cite this article in press as: Hoppenbrouwers SS, et al., Inhibitory deficits in the dorsolateral prefrontal cortex in psychopathic offenders, Cortex (2012), http://dx.doi.org/10.1016/j.cortex.2012.06.003

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was used (Cui et al., 1999; Daskalakis et al., 2008a) whereas for measurement of CEPs from the DLPFC electrode AF3 was used (Herwig et al., 2003; Farzan et al., 2009, 2010; Voineskos et al., 2010; Hoppenbrouwers et al., 2010; Daskalakis et al., 2008a).

2.6.

Working memory

The letterenumber sequencing (LNS) test from the WAIS-III reliably measures working memory performance (Crowe, 2000; Tulsky and Zhu, 2000). In this test a list of random numbers and letters are read out loud to the participant who is then asked to repeat back the numbers and letters. The letters and numbers are presented in alternating order with difficulty increasing across blocks of trials. Subjects are instructed to first say the numbers in order from smallest to biggest and then the letters in alphabetical order. For every correct sequence one point is given amounting to a maximum score of 24.

2.7.

Medication

Two psychopathic offenders used methadone as a treatment for previous opioid addiction (i.e., heroin). One of these offenders also used pantoprazole for gastroesophageal reflux disease. Two offenders received quarterly intramuscular depots of leuprolide (for reduction of testosterone levels) due to repeated sexual offenses. Last, two offenders occasionally used quetiapine as needed for sleeping purposes but selfreports indicated that they had not used this medication in the two weeks prior to TMS assessment.

2.8.

Data analyses

A multivariate General Linear Model (GLM) was conducted with LICI over the DLPFC and primary motor cortex (M1) as dependent variables and Group (psychopaths vs controls) as a fixed factor. To check for differences in cortical excitability, a second multivariate GLM was conducted with CEP over M1 and DLPFC in response to single pulse TMS as dependent variables and Group (psychopaths vs controls) as a between-subjects factor. Independent samples t-tests were performed to check for differences in LNS scores, LICI measured over the APB, MT (with and without EEG cap), and intensity to achieve a MEP of 1 mV peak-to-peak. In order to exclude a confounding influence of methadone on CI (Fingelkurts et al., 2007, 2009) post-hoc analyses were conducted without the methadone treated subjects. Last, separate univariate GLMs were done to check for differences between sham-corrected and sham-uncorrected CI. The PCL-R is composed of two factors; Factor 1, the interpersonal/affective factor and Factor 2, the deviant lifestyle. Pearson’s product moment correlation coefficient was used to check for correlations between LNS scores and LICI over the DLPFC and M1 and to check for a correlation between overall PCL-R scores, Factor 1 and 2 and CI over the DLPFC. Alpha level of significance was set at .05.

3.

in the psychopathy group 15% of all trials were deleted due to TMS, movement or eye blink artifacts.

3.1.

CI

The multivariate GLM showed a significant group effect for the difference in CI measured on EEG, F(2,25) ¼ 4.807, p ¼ .017, h2p ¼ .278. Test of between-subjects effects showed that psychopathic offenders demonstrated significantly lower CI over the DLPFC, F(1,26) ¼ 9.229, p ¼ .005, h2p ¼ .262 but not over the M1, F(1,26) ¼ 2.238, p ¼ .147, h2p ¼ .079 (see Fig. 1). The second multivariate GLM showed no differences in CEPs in response to single pulse TMS between controls and psychopaths, F(2,25) ¼ .482, p ¼ .623. Psychopathic offenders showed no difference in LICI measured from the APB muscle compared to controls, t(27) ¼ .808, p ¼ .426. The post-hoc multivariate GLM that was conducted without the methadone treated subjects to exclude methadone treatment as a potential confound also yielded a significant group effect, F(2,23) ¼ 4.076, p ¼ .029, h2p ¼ .246 and test of betweensubjects effects showed that psychopathic offenders demonstrate significantly lower LICI over the DLPFC, F(1,25) ¼ 8.468, p ¼ .007, h2p ¼ .246, but not over M1, F(1,25) ¼ 2.060, p ¼ .163, h2p ¼ .073. LICI measured from the APB muscle did also not reach significance after excluding the methadone treated subjects, t(24) ¼ .327, p ¼ .746.

3.2.

LNS

Compared to controls, psychopaths performed significantly worse on the LNS test, t(26) ¼ 3.063, p ¼ .005. In healthy controls performance on the LNS test correlated with LICI over the DLPFC (r ¼ .679, p ¼ .005) (see Fig. 2A) but not with LICI over M1(r ¼ .114, p ¼ .685). In psychopaths, performance on the LNS test showed a trend toward a significant correlation with LICI over the DLPFC (r ¼ .519, p ¼ .069) (see Fig. 2B) but not with LICI over M1 (r ¼ .114, p ¼ .685). Neither LNS nor CI over the DLPFC correlated with the PCL-R or with Factor 1 or 2 of the PCL-R, all p values > .110.

Results

TMS was well-tolerated by all subjects without any adverse events. In the control group 10% of all trials were deleted and

Fig. 1 e This figure shows that psychopathic offenders present with significantly less CI on the DLPFC. The error bars represent the SDs.

Please cite this article in press as: Hoppenbrouwers SS, et al., Inhibitory deficits in the dorsolateral prefrontal cortex in psychopathic offenders, Cortex (2012), http://dx.doi.org/10.1016/j.cortex.2012.06.003

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Fig. 2 e A. Stronger CI in the DLPFC is associated with better working memory performance in healthy controls. This correlation shows the importance of GABAergic interneurons in the DLPFC in cognitive processing, specifically in WM. B. This figure depicts the correlation between CI in the DLPFC and WM performance in psychopathic offenders. The data shows a strong trend toward significance although the correlation is not statistically significant.

3.3.

MT

Controls and psychopaths did not differ in MT without cap [t(26) ¼ .550, p ¼ .587] or in MT with cap [t(26) ¼ 1.340, p ¼ .192]. No differences in intensities necessary to reach 1 mV peak-to-peak without cap [t(26) ¼ 1.723, p ¼ .097] or with cap [t(26) ¼ .401, p ¼ .691] were observed.

3.4.

Sham

In a subset of both the control and psychopathy group (6 subjects per group) sham stimulation was applied to control for TMS click-induced auditory activation on the CEPs. For sham stimulation the coil was angled at 90 from the cranium resting on one wing of the coil. Sham stimulation did not significantly change CI in the M1 (in psychopaths; CIactive ¼ 16.1%  43.9% vs CIsham ¼ 18.8%  48.4%, p ¼ .112; in controls; CIactive ¼ 31.2%  37.5% vs CIsham ¼ 50.6%  21.3%, p ¼ .199) or DLPFC (in psychopaths; CIactive ¼ 17.3%  15.9% vs CIsham ¼ 28.7%  60.9%, p ¼ .612; in controls; CIactive ¼ 41.1%  19.5% vs CIsham ¼ 48.9%  19.7%, p ¼ .544).

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Discussion

Through combined TMS and EEG we demonstrate that psychopathy is associated with deficient inhibition in the DLPFC (see Fig. 3). The relationship between inhibition in the DLPFC and working memory that was previously reported (Daskalakis et al., 2008b) was also replicated in healthy subjects but was disrupted in psychopathic offenders which may, in part, explain the behavioral and emotional disinhibition observed in these individuals. The DLPFC has been proposed to control subcortical areas (e.g., amygdala and brainstem) that are involved in the experience of aggressive impulses (Coccaro et al., 2011). Damage to the DLPFC may then result in impulsive-reactive aggression. This is reflected in the observation that psychopathic offenders are not only capable of instrumental aggression, but also display increased levels of reactive aggression (Blair, 2010). Individuals that show more reactive aggression are disinhibited and aggress without consideration of the outcomes of their actions (Coccaro et al., 2011). Furthermore, the importance of intact functioning of the DLPFC is highlighted by a recent study by Boy et al. (2011) in which they show that GABA concentrations in the DLPFC correlate negatively with ‘trait urgency’, one of four facets of impulsivity. Trait urgency, or ‘rash impulsivity,’ is defined as ‘the tendency to act rashly in response to distress or other strong emotions and urges’ and is related to drug abuse, aggression and risky sexual behavior (Boy et al., 2011). The paired pulse TMS paradigm that was used in this study taps into GABAergic neurotransmission, particularly GABAB receptor-mediated inhibitory neurotransmission (McDonnell et al., 2006), and suggests that GABAB receptor-mediated neurotransmission in the DLPFC may be dysfunctional in psychopathic offenders. Consistently, in offenders with a history of conduct disorder baclofen, a GABAB receptor agonist, induces a reduction in aggressive responses which suggests an important role of GABAB in the regulation of aggressive behavior (Cherek et al., 2002). The current finding corroborates the study by Cherek et al. (2002) by showing that GABAB receptor functioning in offenders is indeed abnormal. Together these findings suggest that GABAB receptor-mediated inhibitory neurotransmission in the DLPFC in psychopathic offenders is likely to contribute significantly to their behavioral disinhibition and aggressive behavior. Working memory performance is impaired in psychopathic offenders which is demonstrated by poorer performance on the LNS test. However, the somewhat disrupted correlation between CI in the DLPFC and working memory performance can also be considered evidence for reduced cognitive functioning in psychopathic offenders. Recently, higher-order cognitive functions (e.g., attention and working memory) in psychopathy have gathered more interest (Baskin-Sommers et al., 2011; Newman et al., 2010; Zeier et al., 2009) and have been shown to influence personality features of the psychopath (Newman et al., 2010). For instance, reduced cognitive control has been shown to relate to psychopathic traits (Sadeh and Verona, 2008), specifically secondary psychopathy. Secondary psychopathy is characterized by high levels of impulsivity, irresponsibility and lack of planning whereas the primary psychopath displays a callous, narcissistic and manipulative personality style

Please cite this article in press as: Hoppenbrouwers SS, et al., Inhibitory deficits in the dorsolateral prefrontal cortex in psychopathic offenders, Cortex (2012), http://dx.doi.org/10.1016/j.cortex.2012.06.003

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Fig. 3 e This figure represents LICI averaged over all subjects in each group. The ‘hot’ colors represent strong inhibition whereas ‘cooler’ colors show a lack of inhibition or facilitation. Psychopaths show less CI as compared to healthy controls. Topographic headplots were created with EEGLAB toolbox (Delorme and Makeig, 2004).

(Newman et al., 2005). Patients with antisocial personality disorder have a broad range of cognitive deficits related to DLPFC functioning (Dolan and Park, 2002). Research using the Psychopathic Personality Inventory (PPI) (Lilienfeld and Andrews, 1996), a questionnaire that approaches psychopathy as a cluster of extreme scores on normal personality traits, shows that deficits in cognitive control are related to the social deviance subfactor of the PPI (Sellbom and Verona, 2007; Raine et al., 1998). These findings suggest that poor cognitive functioning is associated with poor regulation of emotion and behavior which, in concert with subcortical deficits (Coccaro et al., 2011), may result in impulsivity and reactive aggression. In line with our suggestion that reduced DLPFC dysfunction results in increased behavioral and emotional disinhibition, reduced WM capacity may reflect an important cognitive function through which DLPFC dysfunction predisposes to impulsive and aggressive behavior. Related to this issue, is the close connection between working memory and goal-directed attention. Psychopathic offenders have difficulty reallocating attention once they have initiated goal-oriented behavior (Bernstein et al., 2000). That is, psychopathic offenders show an interesting impairment in paying attention to information that is peripheral to their ongoing principal behavior. This may result in a rigidity toward continuing with their predominant response set (Baskin-Sommers et al., 2011; Hiatt et al., 2004; Vitale et al.,

2007). As a corollary, psychopathic offenders have difficulty regulating their behavior based on emotionally relevant information while they are engaged in goal-directed behavior. It could be argued, therefore, that DLPFC dysfunction leads to such regulation deficits as it closely involved in both working memory (Daskalakis et al., 2008b; Goldman-Rakic, 1995) and goal-directed attention (Corbetta and Shulman, 2002). Our findings may also help provide a rationale for novel treatment approaches for specific deficits in psychopathy. High frequency (e.g., 20 Hz) repetitive TMS (rTMS), is capable of increasing CI, particularly in subjects that have lower baseline CI (Daskalakis et al., 2006). Research using rTMS over the left DLPFC has suggested that rTMS may work as a cognitive enhancer in psychiatric populations (Barr et al., 2009). rTMS may be employed as a treatment to normalize CI in the DLPFC and WM performance which may enable psychopaths to better control their behavior. However, high frequency rTMS diminishes attention for angry facial expression in healthy volunteers (De Raedt et al., 2010) which has been suggested to predispose to antisocial behavior (van Honk and Schutter, 2007). Therefore, in order to avoid aggravating the psychopath’s antisociality brain stimulation studies in psychopathic offenders should be conducted very cautiously and should be closely monitored. Some limitations of the present study should be mentioned. First, high incidence of drug abuse is common to many psychiatric disorders and it is certainly prevalent in

Please cite this article in press as: Hoppenbrouwers SS, et al., Inhibitory deficits in the dorsolateral prefrontal cortex in psychopathic offenders, Cortex (2012), http://dx.doi.org/10.1016/j.cortex.2012.06.003

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psychopathy. Unfortunately, the high incidence of previous drug abuse (87%) in this sample could contribute to the decreased inhibition in the DLPFC (Schiffer et al., 2011) and potentially to decreased WM performance. However, if behavioral disinhibition related to DLPFC dysfunction is indeed an intrinsic component of psychopathy, the high incidence of drug abuse among psychopaths would be predicted by DLPFC dysfunction and could also be a corollary of behavioral disinhibition. Second, researchers have made a distinction between successful and unsuccessful psychopaths (Yang et al., 2005; Ishikawa et al., 2001). In contrast to the successful (non-convicted) psychopaths who are thought to show normal or even superior cognitive functioning, unsuccessful psychopaths have deficiencies in cognitive processing making them more prone to behavioral disinhibition and overt violence (Gao and Raine, 2010). The current findings may therefore only represent cognitive abilities in unsuccessful psychopathic offenders. Importantly, unsuccessful psychopathic offenders report higher rates of childhood abuse (Gao et al., 2011) which, as was already noted by McCord and McCord (1964), may contribute to the pathogenesis of an emotionally cold and aggressive personality style. In fact, research has shown childhood abuse to result in prefrontal cortical thinning (van Harmelen et al., 2010; Tomoda et al., 2009) which could potentially contribute to dysfunction of inhibitory activity. In our sample 40% of the psychopathic offenders reported a history of childhood abuse, i.e., sexual, physical or verbal abuse. Therefore, the question remains whether DLPFC dysfunction is innate to behavioral disinhibition in psychopathy or whether it is also partly a function of environment. Third, CI measured in the M1 in psychopathic offenders also suggests inhibitory deficits but, given the relatively large variance, does not reach significance. CI indexed from the APB does however not show signs of impairments in inhibition and therefore, it remains unclear whether the motor cortex is also affected in psychopathy. Lastly, evidence shows amygdala (Schiffer et al., 2011; Yang et al., 2010; Jones et al., 2009), orbitofrontal cortex (Yang et al., 2008, 2010; Blair, 2007) ventromedial prefrontal cortex (Motzkin et al., 2011) and uncinate fasciculus (Craig et al., 2009) dysfunction in psychopathy. It is therefore important to emphasize that DLPFC deficits are not likely to be the sole cause of psychopathic disinhibition. Rather, behavioral disinhibition is more likely to result from a complex interplay between deficits in CI, aberrant subcortical activity and hormonal imbalances. In sum, our TMSeEEG study shows impaired CI in the DLPFC and poor working memory performance in psychopathic offenders. Although it is unlikely that deficits in CI and working memory are solely responsible for psychopathic disinhibition, these impairments may very well render the psychopath unable to regulate impulses subjecting them to a disinhibited, antisocial life.

5.

Role of funding source

This work was funded in part by a Canadian Institute of Health Research (CIHR) Clinician Scientist Award, an operating grant from the Ontario Mental Health Foundation, a Constance and Stephen Lieber through a National Alliance

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for Research on Schizophrenia and Depression (NARSAD), Lieber Young Investigator award, and external funding from Neuronetics Inc. and Aspect Medical Inc. and travel support through Pfizer Inc. (ZJD). PBF has received a National Health and Medical Research Council (NHMRC) Practitioner Fellowship and a Constance and Stephen Lieber through an NARSAD Lieber Young Investigator award. PBF has also received external funding from Neuronetics Inc. ZJD and PBF have both received external funding through Neuronetics, Inc. ZJD has received external funding through Aspect Medical, Inc. and travel support through Pfizer, Inc. PBF has received equipment for research studies from MagVenture, A/S and Brainsway, Ltd. DJLGS was supported by an Innovational Research Grant (VIDI 452-07-012) from the Netherlands Organization for Scientific Research (NWO).

6.

Conflict of interest

None.

Acknowledgments The authors thank Yinming Sun and Faranak Farzan for assistance in data analyses and Ginny Hughes for assistance in file reviews.

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