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Association of ventral striatum monoamine oxidase-A binding and functional connectivity in antisocial personality disorder with high impulsivity: A positron emission tomography and functional magnetic resonance imaging study Nathan J. Kollaa,b,c,d,n, Katharine Dunlopd,e, Jonathan Downarc,d,e, Paul Linksd,f, R. Michael Bagbya,c,g, Alan A. Wilsona,b,c,d, Sylvain Houlea,b,c, Fawn Rasquinhaa,b, Alexander I. Simpsonc, Jeffrey H. Meyera,b,c,d a

CAMH Research Imaging Centre, Canada Campbell Family Mental Health Research Institute, CAMH, Canada c Department of Psychiatry, University of Toronto, Canada d Institute of Medical Science, University of Toronto, Canada e University Health Network, Canada f Department of Psychiatry, University of Western Ontario, Canada g Department of Psychology, University of Toronto, Canada b

Received 22 June 2015; received in revised form 7 December 2015; accepted 14 December 2015

KEYWORDS

Abstract

Antisocial personality disorder; Monoamine oxidaseA; Positron emission tomography; Functional magnetic resonance imaging; Impulsivity; Violence

Impulsivity is a core feature of antisocial personality disorder (ASPD) associated with abnormal brain function and neurochemical alterations. The ventral striatum (VS) is a key region of the neural circuitry mediating impulsive behavior, and low monoamine oxidase-A (MAO-A) level in the VS has shown a specific relationship to the impulsivity of ASPD. Because it is currently unknown whether phenotypic MAO-A markers can influence brain function in ASPD, we investigated VS MAO-A level and the functional connectivity (FC) of two seed regions, superior and inferior VS (VSs, VSi). Nineteen impulsive ASPD males underwent [11C] harmine positron emission tomography scanning to measure VS MAO-A VT, an index of MAO-A density, and restingstate functional magnetic resonance imaging that assessed the FC of bilateral seed regions in

n

Corresponding author at: CAMH Research Imaging Centre, Canada. Tel.: +416 535 8501x34248; fax: +416 979 6702. E-mail address: [email protected] (N.J. Kolla).

http://dx.doi.org/10.1016/j.euroneuro.2015.12.030 0924-977X/& 2016 Elsevier B.V. and ECNP. All rights reserved.

Please cite this article as: Kolla, N.J., et al., Association of ventral striatum monoamine oxidase-A binding and functional connectivity in antisocial personality disorder with high.... European Neuropsychopharmacology (2016), http://dx.doi.org/10.1016/j.euroneuro.2015.12.030

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N.J. Kolla et al. the VSi and VSs. Subjects also completed self-report impulsivity measures. Results revealed functional coupling of the VSs with bilateral dorsomedial prefrontal cortex (DMPFC) that was correlated with VS MAO-A VT (r=0.47, p =0.04), and functional coupling of the VSi with right hippocampus that was anti-correlated with VS MAO-A VT (r = 0.55, p =0.01). Additionally, VSsDMPFC FC was negatively correlated with NEO Personality Inventory-Revised impulsivity (r = 0.49, p =0.03), as was VSi-hippocampus FC with Barratt Impulsiveness Scale-11 motor impulsiveness (r = 0.50, p= 0.03). These preliminary results highlight an association of VS MAO-A level with the FC of striatal regions linked to impulsive behavior in ASPD and suggest that phenotype-based brain markers of ASPD have relevance to understanding brain function. & 2016 Elsevier B.V. and ECNP. All rights reserved.

1.

Introduction

Antisocial personality disorder (ASPD) is a serious psychiatric condition that exacts a high healthcare and societal burden due to the impulsive behavior of affected individuals (Scott et al., 2001). Studies parsing impulsivity subtypes in ASPD have identified deficits in behavioral inhibition (Swann et al., 2009) and excessive discounting of delayed rewards (Petry, 2002). Psychopathy is a personality disorder that shares some clinical overlap with ASPD but can be distinguished by its high reliance on the use of proactive or instrumental aggression. The Psychopathy Checklist–Revised (PCL-R) (Hare, 2003), a common tool for assessing psychopathic personality traits, includes impulsivity as a core component of psychopathy (Hare, 2003), although not all individuals with the disorder endorse high impulsiveness or impulsive aggression (Snowden and Gray, 2011). Hence, exploring the neural correlates of ASPD with high psychopathic traits and a history of impulsive violence can refine our knowledge of this specific phenotype. A promising direction to understanding the impulsivity of ASPD with high psychopathic traits that has not yet been explored is to use phenotype-based neurobiological markers that can predict brain function. One marker of interest is monoamine oxidase-A (MAO-A), an enzyme located on outer mitochondrial membranes in glia and neurons that metabolizes monoamine neurotransmitters (Youdim et al., 2006). A growing corpus of animal and human studies points to connections between low or absent brain MAO-A level and impulsive aggression. At least two MAO-A knockout models are associated with high impulsive aggression in adult mice (Cases et al., 1995; Scott et al., 2008). Moreover, males from a Dutch pedigree with deficient MAO-A activity secondary to a non-conservative point mutation of the MAO-A gene were reported to exhibit impulsive, aggressive behavior (Brunner et al., 1993). Two positron emission tomography (PET) studies of healthy humans and one of alcohol dependence have additionally detected relationships between lower widespread MAO-A level and indices of greater impulsivity and aggression (Alia-Klein et al., 2008; Matthews et al., 2014; Soliman et al., 2011). Most recently, low brain MAO-A has emerged as a candidate endophenotype of ASPD with high psychopathic traits and impulsive violence (Kolla et al., 2015). As activation of brain networks implicated in impulsive behavior may be influenced by MAOA genotype (Clemens et al, 2015), it seems logical to examine phenotypic MAO-A markers in relation to other

markers of brain activity that may underlie the impulsivity of ASPD. Resting-state functional magnetic resonance imaging (fMRI) is another technique that can be applied to identify a potential nexus between clinically impulsive phenotypes and patterns of neural functioning. Few resting state fMRI studies of ASPD/psychopathic populations have been reported in the literature. One investigation of young ASPD offenders found decreased resting-state brain activity in temporal and frontal regions (Liu et al., 2014), while three seed-based resting-state analyses of psychopathic samples reported reduced resting-state cortical-subcortical (Contreras-Rodriguez et al., 2015; Motzkin et al., 2011) and cortical-cortical functional connectivity (FC) (Philippi et al., 2015). One of these studies (Contreras-Rodriguez et al., 2015) provided information on a self-report measure of impulsivity but did not examine FC in relation to this symptom. Despite the strong association of impulsivity with violence in antisocial populations (Blackburn and Coid, 1998), very little is known about the FC of brain regions subserving impulsive behavior in ASPD. Considerable pharmacological evidence links brain dopaminergic systems to facilitation of aggressive behavior. Increased dopamine turnover is observed in the nucleus accumbens of rodents engaging in aggressive behavior (Haney et al., 1990; Louilot et al, 1986). Further, optogenetic stimulation of dopaminergic neurons in mouse midbrain has been shown to induce protracted aggressive responding (Yu et al., 2014). In a sample of violent offenders, cerebrospinal fluid dopamine metabolites predicted psychopathic traits and were most strongly related to items tapping behavioral measures on the PCL-R (Soderstrom et al., 2001). Impulsive-antisocial psychopathic traits are also associated with enhanced activity of mesolimbic dopaminergic neurons to pharmacological reward (Buckholtz et al., 2010). By contrast, a 6-[18F]-fluoro-L-DOPA PET study of healthy subjects reported an inverse correlation between striatal dopamine synthesis capacity and impulsive aggressive responding following provocation (Schlüter et al., 2013). Since MAO-A expression and activity are highly correlated in the striatum (Meulendyke et al., 2014; Tong et al., 2013), and MAO-A inhibition leads to increased striatal dopamine level (Yu et al., 2014), a plausible mechanism to account for increased striatal dopaminergic tone in impulsive aggression is lower co-localized MAO-A activity. The VS is a core component of the cortico-limbic-striatal neurocircuitry that receives input from the midbrain

Please cite this article as: Kolla, N.J., et al., Association of ventral striatum monoamine oxidase-A binding and functional connectivity in antisocial personality disorder with high.... European Neuropsychopharmacology (2016), http://dx.doi.org/10.1016/j.euroneuro.2015.12.030

Association of ventral striatum monoamine oxidase-A binding and functional connectivity dopaminergic system and is implicated in multiple forms of impulsive responding (Basar et al., 2010; Dalley et al., 2011; Dalley et al., 2007). Critically, functional alterations of the VS are associated with impulsivity in antisocial populations (Glenn and Yang, 2012), and VS MAO-A level shows a specific, negative correlation with the impulsivity of ASPD (Kolla et al., 2015). Therefore, the present study was driven by the hypothesis that VS MAO-A total distribution volume (VT), an index of MAO-A density measured using [11C] harmine PET (Ginovart et al., 2006), would be associated with VS FC, assessed using resting-state fMRI, in a sample of impulsive males with ASPD. We hypothesized that VS MAO-A VT would show a relation with the FC of seed regions in both inferior and superior VS and that these associations would correlate with self-report measures of impulsivity.

2.

Experimental procedures

Nineteen males with ASPD completed the study protocol. Each participant provided written consent following explanation of study procedures. All study components were approved by the Research Ethics Board for Human Subjects at the Centre for Addiction and Mental Health (CAMH), Toronto, Canada.

2.1.

Participants

Subjects were recruited from the community and probation services. All participants were clinically assessed by a forensic psychiatrist (NJK) and diagnosed using the SCID-II (First et al., 1997) and SCID I (First et al., 2002). All subjects were additionally administered the Wechsler Test of Adult Reading that provided an estimate of full-scale IQ (Wechsler, 2001). Each ASPD participant had a history of impulsive violent offending that included manslaughter, assault, sexual assault, robbery, and uttering threats. Exclusion criteria included history of a psychotic, major depressive, or bipolar disorder; current non-alcohol drug abuse or dependence; use of psychotropic medication; and cigarette smoking. Nonsmoking status was determined by breathalyzer testing for carbon monoxide (MicroSmokerlyzer; Bedfont Scientific Ltd., Kent, United Kingdom). Study subjects abstained from tea, coffee, and caffeinated beverages on PET and fMRI scanning days (scans acquired 7.8713.8 days apart). Subjects provided negative urine toxicology screens on all scanning and assessment days.

2.2.

PET imaging

Participants underwent a single [11C] harmine PET scan at the CAMH Research Imaging Centre. The PET data of 18 of the study subjects were presented in a previous study (Kolla et al., 2015). Participants completed a single [11C] harmine PET scan. 370 MBq (10 mCi) of intravenous [11C] harmine was administered as a bolus injection at the beginning of each PET scan. An automatic blood sampling system assessed arterial blood radioactivity continuously for the first 10 min. Thereafter, manual samples were acquired at 2.5, 7.5, 15.0, 20.0, 30.0, 45.0, 60.0 and approximately 90.0 min. Whole blood and plasma radioactivity was quantified as previously described (Ginovart et al., 2006). Fifteen frames lasting 1 min each were acquired, followed by 15 frames of 5 min each. [11C] Harmine was of very high radiochemical purity (98.970.8%) and high specific activity (138.6767.0 GBq [3745.771810.8 mCi]/μmol) at the time of injection. PET images were acquired using a high resolution research tomograph (HRRT) PET camera (in-plane resolution; full width at half maximum, 3.1 mm; 207 axial sections of 1.2 mm; Siemens Molecular Imaging, Knoxville, TN) as previously described (Meyer et al., 2009).

2.3.

3

Image Analysis

Each participant also underwent a T1-weighted anatomical scan (TE=3.0 ms, TR=6.7 ms, flip angle=81, slice thickness=0.9 mm, 200 slices, FOV =240 mm, matrix=256  256, voxel size =0.9 mm  0.9 mm  0.9 mm; 3.0-T GE Discovery MR750 scanner; GE Medical Systems, Milwaukee, WI) for the region of interest (ROI) analysis. The ROI was determined using a semi-automated method: regions of a template MRI were transformed onto the individual MRI according to a series of transformations and deformations that fit the template image to the individual co-registered MRI; next, the individual MRI was segmented to select gray matter voxels, as previously reported (Meyer et al., 2009; Rusjan et al., 2006).

2.4.

ROI selection

The VS was chosen as the primary PET ROI, because this region is associated with the neurocircuitry of impulsivity (Basar et al., 2010; Dalley et al., 2007) and functional abnormalities of the VS are specifically related to the impulsivity of ASPD (Kolla et al., 2015). The boundaries of the VS were based on the definition reported by Mawlawi and co-investigators (Mawlawi et al., 2001), which provides a robust PET time activity curve for this region. 2.4.1. MAO-A VT MAO-A VT signifies the total tissue binding of [11C] harmine at equilibrium and correlates highly with MAO-A level (Ginovart et al., 2006; Tong et al., 2013). Both the unconstrained two-tissue compartment model and Logan model (Logan et al., 1990) with arterial sampling, for which the underestimate of VT is minimal, measure VT with high reliability and validity. In the present study, the Logan model was applied (Ginovart et al., 2006; Logan et al., 1990).

2.5.

Resting-state fMRI

2.5.1. Image acquisition Each participant completed a 6-minute fMRI scan (TE=30 ms, TR =2000 ms, flip angle=601, slice thickness=5.0 mm, 31 axial slices, FOV=220 mm, matrix=64  64; voxel size =3.4 mm  3.4 mm  5.0 mm) performed in the resting state with eyes closed. Functional images were obtained from the same scanner used to acquire the structural scan for the PET ROI analysis. This same structural scan was also used for spatial normalization and localization of the functional MRI scans.

2.6.

Image preprocessing

Preprocessing of resting-state functional neuroimaging data was carried out using the FMRIB software library (http://www.fmrib.ox. ac.uk/fsl/). The first five volumes were discarded to allow for T1 equilibrium effects. Preprocessing steps included slice-time correction, removal of non-brain tissue using the Brain Extraction Tool (BET) (Smith, 2002), spatial smoothing using a Gaussian kernel of 6 mm FWHM, and mean-based intensity normalization by a single multiplicative factor of all images. Six motion parameter time series (3 translational and 3 rotational parameters) were included as covariates of no interest in the general linear model (GLM), and the aCompCor method (Behzadi et al., 2007) was applied using an in-house MATLAB-based script to correct for cerebrospinal and white matter noise sources. De-noised scans were bandpass filtered between 0.009 and 0.9 Hz. fMRI volumes were registered to each participant’s structural scan and the MNI-152 stereotactic space using the Linear Image Registration Tool (FLIRT) (Jenkinson et al., 2002; Jenkinson and Smith, 2001).

Please cite this article as: Kolla, N.J., et al., Association of ventral striatum monoamine oxidase-A binding and functional connectivity in antisocial personality disorder with high.... European Neuropsychopharmacology (2016), http://dx.doi.org/10.1016/j.euroneuro.2015.12.030

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N.J. Kolla et al.

2.7.

Seed region of interest selection

impulsive behaviors (Parker and Babgy, 1997). Thus, these instruments likely capture different aspects of impulsivity.

Two seed ROIs in the VS were manually selected in standard space: bilateral ventral striatum superior (VSs) and bilateral ventral striatum inferior (VSi). The VSs seed included the ventral caudate (MNI: x =710, y =15, z =0, with 3 mm radius), and the VSi seed included both ventral caudate and nucleus accumbens (MNI: x=79, y=9, z = 8, with 3 mm radius). The VS seed coordinates were derived from a previous study (Di Martino et al., 2008) that assessed striatal FC patterns. Both seeds were tested, because the VS ROI used for the PET analysis encompassed both inferior and superior ventral striatal regions (Mawlawi et al., 2001).

2.9.3. PCL-R The PCL-R (Hare, 2003) is a clinical construct that operationalizes psychopathy based on personality and behavioral items that load onto two factors. Factor 1 indexes interpersonal and affective characteristics, while factor 2 comprises features related to social deviance, including impulsivity. The PCL-R includes 20 items that are rated from 0–2 (0=absence of trait; 1=some features of the trait; 2 =definite presence of the trait) to generate a total score between 0 and 40.

2.8.

2.10. Statistical analysis

Statistical analysis of fMRI data

Seed ROIs were registered to each subject’s functional space utilizing the transformation matrix from the initial registration to standard space in FLIRT. Average time courses for each masked ROI were extracted and fit with a GLM to detect correlated and anticorrelated voxels associated with the seed ROI. These correlations with the time series were interpreted as the degree of FC with each seed region for every subject. To identify voxels whose correlation with the ROI time series was associated with MAO-A VT, the spatially normalized effect size and standard error volumes provided input to a group analysis using FSL’s FLAME mixed effect model (Beckmann et al., 2003). Demeaned VS MAO-A VT values for each subject were included as regressors in two GLMs that fit correlated voxels with the VSs or VSi seed time series. The modeled group effect sizes and standard errors for each of the two GLMs were divided to yield volumes that were T scores. T scores were then transformed to Z scores. Corrections for multiple comparisons were carried out using Gaussian random field theory cluster-based correction (Z41.98, cluster significance po0.05, corrected), which generated corrected Z-score maps correlating the FC of each seed (VSi or VSs) to MAO-A VT. Single-subject connectivity values between seed and target regions for the group level analyses were extracted by transforming masks of defined clusters into individual space and obtaining Zscore values from the connectivity map of interest. To ensure anatomical specificity of the extracted regions, the target region was masked with the anatomical map from the Harvard-Oxford atlas (50% probability).

2.9.

Clinical measures of impulsivity

2.9.1. Barratt Impulsiveness Scale-11 The Barratt Impulsiveness Scale-11 (BIS-11) is a self-report instrument indexing an impulsivity construct that consists of three subscales: motor impulsiveness, attentional impulsiveness, and nonplanning impulsiveness (Patton et al., 1995). In a sample of prisoners, the intraclass coefficient of the BIS-11 was reported as 0.80 (Patton et al., 1995). Moreover, the motor impulsiveness subscale has been shown to discriminate clinically impulsive groups from healthy controls (Nasser et al., 2004). 2.9.2. NEO Personality Inventory-Revised The NEO Personality Inventory-Revised (NEO PI-R) (Costa Jr. and McCrae, 1992) is an extensively validated questionnaire based on the five-factor model of personality that can index normal and abnormal personality functioning (Goldberg, 1990). The NEO PI-R provides norm-referenced test scores for higher and lower order personality factors, including impulsivity. Whereas the BIS-11 describes a construct that is compatible with personality traits of extraversion and sensation seeking (Whiteside and Lynam, 2001), items comprising the NEO PI-R impulsiveness subscale assess a very circumscribed component of impulsivity, namely failure to control

Pearson's correlation coefficients were used to measure the strength of the associations between observed FC patterns and measures of impulsivity. Estimated full-scale IQ was included as a covariate in these analyses given the relationship between IQ and FC (van den Heuvel et al., 2009) and IQ and impulsivity (de Wit et al., 2007).

3. 3.1.

Results Subject characteristics

Clinical and demographic characteristics of the sample are presented in Table 1. Subjects were aged 18 to 48 years. The mean NEO PI-R impulsivity score of the sample was approximately one standard deviation higher than the normative male population (Costa Jr. and McCrae, 1992), indicative of high impulsivity. The total BIS-11 score (80.1) of the participants was comparable to the mean score of a prison inmate sample (76.3) included in a factor analysis of the BIS-11 (Patton et al., 1995). The mean PCL-R score in a sample of healthy males was o11 (Ishikawa et al., 2001), which is considerably lower than the mean PCL-R score of the present sample (26.3).

3.2.

FC

Correlations were detected between the FC of both VS seed regions and VS MAO-A VT from the same regions. 3.2.1. VSs seed Examination of FC during resting-state conditions revealed patterns of connectivity between VSs and frontal cortical regions, including bilateral dorsomedial prefrontal cortex (DMPFC), bilateral pre- and post-central gyrus, and right superior frontal gyrus, that were correlated with VS MAO-A VT (r=0.47, corrected p= 0.04, R2 = 0.23; correlation with bilateral DMPFC). No FC involving the VSs seed was anticorrelated with VS MAO-A VT (see Figure 1 and Table 2). 3.2.2. VSi seed The VSi seed predicted patterns of activity in limbic regions (e.g., right hippocampus and parahippocampal gyrus) and posterior cortical regions, such as superior/middle temporal gyrus and occipital cortex, that were anti-correlated with VS MAO-A VT (r= 0.55, corrected p= 0.01, R2 =0.31; correlation with right hippocampus and parahippocampal gyrus). No FC involving the VSi seed was correlated with VS MAO-A VT (see Figure 2 and Table 2).

Please cite this article as: Kolla, N.J., et al., Association of ventral striatum monoamine oxidase-A binding and functional connectivity in antisocial personality disorder with high.... European Neuropsychopharmacology (2016), http://dx.doi.org/10.1016/j.euroneuro.2015.12.030

Association of ventral striatum monoamine oxidase-A binding and functional connectivity

Table 1 Clinical Characteristics of Antisocial Personality Disorder Subjectsa. Characteristics

ASPD (n= 19)

Age Ethnicity % Caucasian % African Canadian % Asian % Other Estimated full-scale IQ Education, years VS MAO-A VT Impulsivity measures BIS-11 Motor impulsiveness Nonplanning impulsiveness Attentional impulsiveness NEO PI-R impulsivity (T-score) Antisociality measures Number of conduct disorder symptoms Number of ASPD symptoms PCL-R Total score PCL-R factor 1 score PCL-R factor 2 score PCL-R impulsivity score

36.0 (9.1) 47.4 26.3 10.5 15.8 105.7 (10.9) 13.9 (2.4) 18.2 (3.1)

30.3 30.7 19.1 59.1

(4.3) (6.8) (5.7) (13.0)

7.7 (3.6) 5.6 (1.2) 26.3 (6.6) 9.5 (3.2) 14.7 (3.8) 1.8 (0.4)

a

Values are expressed as mean (standard deviation) or percentages; ASPD=antisocial personality disorder; BIS -11=Barratt Impulsiveness Scale-11; IQ=intelligence quotient; MAO-A VT =monoamine oxidase-A total distribution volume; NEO PI-R=NEO Personality Inventory-Revised; PCLR=Psychopathy Checklist–Revised; VS=ventral striatum.

To test the specificity of these findings, we investigated the relationship between the FC of the anterior thalamus (Behrens et al., 2003) and thalamus MAO-A VT. Similar to the FC of the VSs, patterns of connectivity between thalamus and bilateral pre/postcentral gyrus (x= 2, y= 32, z=50, Z-score=3.20) were positively correlated with thalamus MAO-A VT. Connectivity patterns of the VS and thalamus seeds with MAO-A VT showed no additional overlap.

3.3. Relationship between VS MAO-A VT, VS FC, PCL-R scores, and impulsivity VS MAO-A VT was negatively correlated with NEO PI-R impulsivity (r= 0.45, p= 0.05). In other words, subjects who self-reported greater impulsivity had lower VS MAO-A VT. VS MAO-A VT did not show significant or trend correlations with any of the BIS-11 subscales. An inverse correlation was detected between VS MAO-A VT and PCL-R impulsivity (r = 0.59, p= 0.008) but not total PCL-R score (p= 0.43), PCL-R factor 1 score (p= 0.94), or PCL-R factor 2 score (p= 0.42). As would be expected, results indicated that DMPFC-VSs FC was negatively correlated with NEO PI-R impulsivity (r= 0.49, p =0.03), while hippocampal-VSi

5

connectivity was negatively correlated with BIS-11 motor impulsivity (r = 0.50, p= 0.03) (see Table 3).

4.

Discussion

To the best of our knowledge, this is the first study to link an in vivo MAO-A brain imaging marker to another marker of functional brain activity. We focused our analyses on the VS in ASPD, because low VS MAO-A VT has shown a robust and specific relationship to several indices of impulsivity in this population (Kolla et al., 2015). We found that the FC of inferior and superior VS seed regions was associated with VS MAO-A VT, which implies that low VS MAO-A level may be relevant to the FC of these brain regions. Among the functions of human MAO-A, we suggest that its role in metabolizing dopamine is most relevant to understanding our results. These findings shed new light on the relationship between brain MAO-A and striatal-based FC in ASPD and indicate a potential role for MAO-A as a neuromodulatory influence on neural circuits underlying impulsive behaviors. One of our two principal findings is that VS MAO-A VT was correlated with DMPFC-VSs FC. In addition, we found that VSs-DMPFC FC was negatively correlated with NEO PI-R impulsivity. This finding is consistent with a recent investigation describing reduced functional coupling between prefrontal regulatory regions and subcortical drive structures, including caudate and nucleus accumbens, as a function of increasing self-reported trait impulsivity (Davis et al., 2013). Interestingly, administration of L-dopa to healthy subjects has been shown to decrease FC between ventral caudate and cortical structures (Kelly et al., 2009), and clinical samples of impulsive subjects exhibit greater striatal dopamine release following amphetamine challenge that is associated with diminished inhibitory control (Cherkasova et al., 2014). Since dopamine exhibits high affinity substrate binding to MAO-A (O'Carroll et al., 1983) and MAO-A inhibition stimulates dopamine release from the VS (Finberg et al., 1995), our results point to VS MAO-A as a possible influence on dopaminergic signaling in the VS that is linked to reduced DMPFC-VSs FC and greater impulsiveness. This model accords well with previous findings of lower VS resting activity and increased striatal dopamine release in impulse control disorders (Rao et al., 2010; Steeves et al., 2009) and outlines a novel mechanism to describe the neural underpinnings of pathological impulsivity in ASPD. While the present study cannot inform on the extent to which the observed FC patterns were modulated by VS dopamine levels, the results tentatively suggest that activation of corticostriatal pathways implicated in impulsive behavior may relate to VS MAOA level. The second main finding is that VS MAO-A VT was anticorrelated with hippocampus-VSi FC. In keeping with a model proposing a neuromodulatory action of VS MAO-A on dopaminergic input to VS FC, the nucleus accumbens receives excitatory input from the hippocampus under rewarding conditions and amplifies phasic dopamine release to maintain goal-directed behavior (Sesack and Grace, 2010). These findings resonate with clinical and behavioral data highlighting faulty reward processing in ASPD (Petry, 2002) and bridge observations of elevated amphetamine-induced dopamine release in impulsive/antisocial traits (Buckholtz et al.,

Please cite this article as: Kolla, N.J., et al., Association of ventral striatum monoamine oxidase-A binding and functional connectivity in antisocial personality disorder with high.... European Neuropsychopharmacology (2016), http://dx.doi.org/10.1016/j.euroneuro.2015.12.030

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N.J. Kolla et al.

Figure 1 Table 2 Seed

Superior ventral striatum connectivity is correlated with VS MAO-A VT.

Activation peaks for regions where VSi and VSs resting state FC were associated with VS MAO-A VT. Functional region

Brodmann area

MNI x

Vsi

VSs

Anticorrelated with MAO-A VT Parahippocampal gyrus, hippocampus Intracalcarine sulcus Lateral occipital cortex, superior/middle temporal gyrus Lateral occipital cortex, middle temporal gyrus Correlated with MAO-A VT Pre/postcentral gyrus Dorsomedial prefrontal cortex Superior frontal gyrus

y

Peak Z-score z

17, 18 19, 22, 39 19, 22, 39

20 6 64 56

28 92 24 68

6 18 2 18

3.12 3.24 4.02 3.93

3, 4, 5, 6 8 6

10 8 18

32 40 22

58 50 44

4.72 3.28 4.33

FC=functional connectivity; MAO-A VT =monoamine oxidase-A total distribution volume; MNI=Montreal Neurological Institute coordinates; VSi=ventral striatum inferior; VSs =ventral striatum superior. Note: Z-scores indicate the degree of correlation between connectivity and MAO-A VT. Peaks are from significant clusters (po0.05, corrected).

2010) with greater reward-related VS activation in antisocial groups (Pujara et al., 2014). The inverse correlation detected between VSi-hippocampal FC and motor impulsivity in the present study is intriguing in the context of animal research demonstrating that hippocampus-lesioned rats make more impulsive choices (Cheung and Cardinal, 2005) and that violent, impulsive offenders exhibit decreased resting state hippocampus metabolism (Soderstrom et al., 2000). Accordingly, our results support the interpretation that weakened striatal-hippocampal functional connections in ASPD relate to

VS MAO-A level and may comprise a neural substrate of pathological impulsivity in this population. Several fMRI-genetic studies in healthy males have reported correlations between the low-transcription MAOA genetic variant, personality traits related to impulsivity and anger, and altered activation of brain regions that underlie emotion regulation (Alia-Klein et al., 2009; Denson et al., 2014; Meyer-Lindenberg et al., 2006). Because human MAO-A brain level has not been shown to correspond to in vitro changes in MAO-A (Fowler

Please cite this article as: Kolla, N.J., et al., Association of ventral striatum monoamine oxidase-A binding and functional connectivity in antisocial personality disorder with high.... European Neuropsychopharmacology (2016), http://dx.doi.org/10.1016/j.euroneuro.2015.12.030

Association of ventral striatum monoamine oxidase-A binding and functional connectivity

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Figure 2 Inferior ventral striatum connectivity is anti-correlated with VS MAO-A VT.

et al., 2007), the findings of the aforementioned studies suggest that effects induced by lower MAO-A gene expression may be most relevant during early maturation of brain networks (Alia-Klein et al., 2009; Denson et al., 2014; Meyer-Lindenberg et al, 2006). On the other hand, the advantage of the present investigation is that we were able to demonstrate a link between a regionally-specific in vivo neurochemical marker and FC of the same anatomic region. The clinical importance of this research is highlighted by findings that neural patterns of self-regulation are strengthened in some individuals with externalizing behaviors who show a good treatment response to behavioral interventions (Woltering et al., 2011). Should future research delineate a relationship between brain MAO-A level and alteration of neural circuits associated with enhanced self-regulation, these findings would provide a catalyst to investigate how manipulation of in vivo MAO-A brain expression may influence neural markers linked to improvement in impulsive and externalizing behaviors. Our sample comprised ASPD males who manifested high PCL-R psychopathic traits and high impulsiveness, the latter assessed by self-report questionnaires, PCL-R impulsivity item scores, and criminal histories of impulsive violence. Although impulsivity contributes to overall PCL-R score, VS MAO-A may relate to impulsivity without showing a relation to other prototypical psychopathic traits, such as factor 1 items that increase risk of instrumental aggression (Woodworth and Porter, 2002). To test these relationships,

we examined VS MAO-A in relation to the PCL-R impulsivity item and PCL-R total and factor scores. We observed a strong negative correlation between VS MAO-A and PCL-R impulsivity and no relationship of VS MAO-A with PCL-R total or factor scores. We interpret these findings to mean that the low brain MAO-A phenotype is most relevant to the impulsive aggression of ASPD with high psychopathic traits. We acknowledge several limitations of the present investigation. The most important is the absence of a control group. Although we demonstrated that VS MAO-A VT was associated with seed-based VS FC in ASPD, we cannot conclude that the observed results are specific to ASPD. Still, we were able to show that a neurochemical phenotype-based marker of ASPD has relevance to understanding functional brain activity associated with high impulsivity. A second limitation is the relatively small sample size. To address this limitation, we confined our analyses to a focal hypothesis that investigated VS MAO-A VT and FC. A third limitation pertains to the high intercorrelation of MAO-A VT across brain regions that could impact specificity of findings. Although some overlap in FC patterns between VS and thalamus seeds as a function of MAO-A VT was observed, VS MAO-A VT predicted functional coupling of VS to cortical and subcortical structures that are implicated in the neurocircuitry of impulsivity. We propose that the functional impact of VS MAO-A VT may be most relevant to understanding VS activation patterns related to the impulsivity of ASPD. A final limitation, common to most

Please cite this article as: Kolla, N.J., et al., Association of ventral striatum monoamine oxidase-A binding and functional connectivity in antisocial personality disorder with high.... European Neuropsychopharmacology (2016), http://dx.doi.org/10.1016/j.euroneuro.2015.12.030

As depicted in the correlation matrix, ventral striatum (VS) monoamine oxidase-A total distribution volume (MAO-A VT) was significantly correlated with the functional connectivity (FC) of inferior ventral striatum (VSi) and superior ventral striatum (VSs) seed regions. The FC of VSi and VSs was additionally negatively correlated with measures of self-reported impulsivity. n po0.05. nn po0.01. nnn po0.001. a T-score; DMPFC=dorsomedial prefrontal cortex; hipp = hippocampus; NEO PI-R=NEO Personality Inventory-Revised.

– – – – – – – – – – – – 0.65nn – – – – – 0.75nnn 0.71nnn – – – – 0.30 0.21 0.41 – – – 0.49n 0.36 0.28 0.18 – – 0.34 0.14 0.27 0.50n 0.40

NEO PI-R impulsivity VSs-DMPFC FC VSi-hipp FC VS MAO-A VT

– 0.55nn 0.47n 0.45n 0.17 0.15 0.05 VS MAO-A VT VSi-hipp FC VSs-DMPFC FC NEO PI-R impulsivitya Barratt attentional Barratt motor Barratt nonplanning

Table 3

Relationship between VS MAO-A VT, VSs/VSi FC, and self-reported impulsivity.

Barratt attentional

Barratt nonplanning

N.J. Kolla et al.

Barratt motor

8

neuroimaging studies of offender populations, is that we limited our investigation to males, which reflects the fact that ASPD is 5-7 times more common in men than women (Hamdi and Iacono, 2014). In conclusion, we have shown for the first time that individual differences in VS MAO-A VT relate to variation in seed-based VS FC among impulsive males with ASPD. These results add to an accumulating evidence base that highlights brain MAO-A as a key molecular target of impulsive aggression in ASPD. The use of multimodal imaging techniques to link a neurochemical disease marker with brain function represents a critical advance to disentangling the neural underpinnings of this poorly understood and challenging clinical condition.

Role of funding source Funding for this study was provided by an operating Grant from the Canadian Institutes of Health Research (CIHR), a CIHR Clinician-Scientist Training Award, and an American Psychiatric Association Psychiatric Research Fellowship. These organizations had no further role in the 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.

Contributiors Drs. Kolla, Meyer, Links, Bagby, Simpson, Houle, and Wilson designed the study. Dr. Kolla, Dr. Meyer, and Ms. Rasquinha were responsible for data collection. Drs. Kolla, Meyer, Houle, and Wilson were involved in the analysis of the PET scan data. Dr. Kolla, Dr. Downar, and Ms. Dunlop contributed to the analysis of the fMRI data. Dr. Kolla wrote the first draft of the manuscript. All authors contributed to and have approved the final manuscript.

Conflict of interest statement Drs. Meyer, Wilson, and Houle have received operating Grant funds for other studies from Eli-Lilly, GlaxoSmithKline, Bristol Myers Squibb, Lundbeck, Janssen, and SK Life Sciences in the past 5 years. Dr. Meyer has consulted to several of these companies as well as Takeda, Sepracor, Trius, Mylan and Teva. Dr. Links received an honorarium from Lundbeck within the past 5 years. None of these companies participated in the design or execution of this study or in writing the manuscript. All other authors report no disclosures.

Acknowledgments We also thank the Campbell Family Mental Health Research Institute; technicians Alvina Ng and Laura Nguyen; chemistry staff Jun Parkes, Armando Garcia, Winston Stableford, and Min Wong; engineers Terry Bell and Ted Harris-Brandts; and students Charis Kellow and Jalpa Patel for their assistance with this project.

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Please cite this article as: Kolla, N.J., et al., Association of ventral striatum monoamine oxidase-A binding and functional connectivity in antisocial personality disorder with high.... European Neuropsychopharmacology (2016), http://dx.doi.org/10.1016/j.euroneuro.2015.12.030