Antisocial developmental Trajectories

Fear conditioning refers to the process in which a previously neutral
conditioned stimulus (CS+) is associated with an aversive and fear-inducing
unconditioned stimulus (US) and becomes intrinsically aversive (Pavlov 1927).
According to Eysenck*s theory of antisocial behaviour development (1977), fear
conditioning is an essential element of moral socialization during normal
development in children. As such, impaired fear conditioning is thought to
hamper moral conscience development and therefore to increase the probability
of antisocial behaviour development. In line with this theory, studies in adult
antisocial populations have shown poorer conditioning, relative to controls
(Hare 1978, Raine 1993). To date, studies in juvenile antisocial populations,
examining whether deficient fear conditioning indeed contributes to the
development and persistence of antisocial behaviour at a young age have been
scarce. Moreover, although new neuroimaging techniques have elucidated the
brain areas and functions involved in fear conditioning in healthy populations,
to date no neuroimaging studies examining fear conditioning have been performed
in juvenile antisocial populations.
In addition to impaired fear conditioning, antisocial populations have been
hypothesized to be characterized by higher sensitivity for reward and lower
sensitivity for punishment as compared with controls (Shapiro et al 1988,
Fowles 1980). While behavioural studies have started to provide evidence for
these phenomena in Disruptive Behaviour Disorder (DBD) children (Matthys et al
2004), more studies are needed to reproduce these findings in juvenile
delinquent populations and to identify the underlying neural mechanisms related
to these characteristics, as these have not been studied to date.
To examine the relationship between the neural substrates (function of relevant
brain areas, connectivity between these areas and their structure) of fear
conditioning as well as reward/punishment sensitivity, and the
development/persistence of juvenile antisocial behaviour, a functional
neuroimaging study is proposed. Subjects will be recruited from a unique large
cohort of adolescents with a history of police contacts below the age of
twelve, who have participated in three previous waves of an ongoing
longitudinal project on juvenile antisocial behaviour development (Van Domburgh
et al 2009). Those participants who have previously been diagnosed with
early-onset DBD will be selected. These early-onset DBD juveniles will be
psychiatrically reassessed for the current proposal, and subdivided in two
subgroups; those who still meet the criteria for a DBD diagnosis (i.e. a
persistent pattern of DBD; DBD-p) versus those who do not meet the criteria for
DBD anymore (i.e. a desistent pattern of DBD; DBD-d). These subgroups will be
compared with healthy controls in a neuroimaging protocol, using a fear
conditioning and reward/punishment anticipation paradigm.
Furthermore, a group of juveniles from the same cohort with subclinical levels
of DBD will be selected to investigate which of these children develop a
persistent pattern of antisocial behaviour and which develop a desistent
pattern. Including children with subclinical levels of DBD will improve the
quality of dimensional (as compared to categorical) analyses and thus increase
clinical relevance of this study. Furthermore, it enhances statistical power to
study biosocial interactions in relation to antisocial development in this
group of early-onset offenders.

We hypothesize that, first, early-onset DBD youngsters will show diminished
fear conditioning, and that this phenomenon will be associated with altered
function, connectivity and structure of brain areas known to be involved in
fear conditioning. Second, we expect these early-onset DBD juveniles to be more
sensitive to reward and less sensitive to punishment, reflected in both
behavioural data and different function, connectivity and structure of
reward/punishment-related brain areas. Third, we expect that the potential
impairments in fear conditioning and reward/punishment sensitivity in
early-onset DBD juveniles will be more pronounced in the DBD-p subgroup as
compared with the DBD-d subgroup. Fourth, we expect that biosocial interactions
add to the proportion of variance in antisocial behaviour explained by main
effects of biological and social risk factors. Finally, we expect that proximal
risk factors such as family characteristics and psychiatric co-morbidity are
the most potent psychosocial predictors of deleterious late-adolescent
outcomes.

In the genetic follow-up (i.e. *Amendement genetica*), the previous MRI study
will be complemented by genetic research. Parallel to the emergence of new
neuroimaging techniques, the field of genetics has made tremendous progress.
Within the last few decades, genetics has seen groundbreaking discoveries and
contemporary scholars acknowledge that many disorders and behaviors have a
genetic predisposition. Several studies have demonstrated that this genetic
liability is also an important contributing factor to the variance in
antisocial behavior. Twin and adoption studies have shown that about half of
the individual differences in antisocial behavior can be explained by genetic
factors. Nevertheless, antisocial behaviour is phenotypically heterogeneous and
of polygenic nature, both of which seriously hamper current etiological
investigations. The proposed research aims to tackle these two issues by using
an innovative, integrated strategy incorporating genetics and imaging. By
relating findings on the level of the brain with findings at the molecular
level, we aim to elucidate the mechanisms underlying the antisocial development
of young individuals. We seek to identify causal mechanisms responsible for
antisocial development.


In the fifth wave of this study ("Amendment Wave 5") a new measurement wave is
included. Central aim is to understand why not all youth with antisocial
behavior with the same initial risk come to the same outcome (ie
multifinality), and even if they do so, they often show different pathways
('equifinality', Odgers et al., 2008). A crucial question that remains open is
unraveling the underlying mechanisms that can explain why some people persist
in displaying antisocial behavior, while others do not (i.e., a declining
trajectory of antisocial behavior in adolescence and adulthood). A better
understanding of the mechanisms that may influence antisocial development will
contribute to the development of effective prevention and intervention programs
(Somma, Andershed, Borroni, Salekin & Fossati, 2018, Lee, 2018). The 12-minners
cohort is now in the age of young adulthood. A period in which we can determine
how these people developed. Based on the network model for social information
processing by Nelson and colleagues (2016), we will investigate three
mechanisms that may unravel the two different development trajectories
(persistent versus desistent): self-concept, (social) reward learning and
impulse control. These processes have been linked to parts of the social brain
network that are sensitive to social experiences and temperament, and therefore
provide a comprehensive assessment of social brain development.

Amendment 'EEG / Justice' concerns the addition of three extra measures to the
Wave 5 measurement that is about to start, namely:
i) 1 additional questionnaire for cyber crime,
ii) applying for judicial / police data to map participants' recidivism via
official register data (self-report antisocial behavior is already included in
the original wave 5 amendment) and
iii) Adding EEG recording to the moral learning task in order to be able to
link the neural correlate (temporal specific) of the moral task to the neural
correlate (spatial specific) on social reward learning. In this way we gain
insight into both the spatial and temporal neural correlates of social learning.


Literature references:

Eysenck HJ. Crime and personality. 1977 (3rd ed.) St. Albans, Hertfordshire,
England: Paladin.

Fowles DC. The three arousal model: implications of gray's two-factor learning
theory for heart rate, electrodermal activity, and psychopathy.
Psychophysiology 1980 17(2): 87-104.

Hare RD. Electrodermal and cardiovascular correlates of psychopathy. In: RD
Hare & D Schalling [eds.] Psychopathic behaviour: approaches to research. 1978
New York: Wiley.

Lee, S. S. (2018). Multidimensionality of youth psychopathic traits: Validation
and future directions. Journal of Psychopathology and Behavioral Assessment,
1-7.

Matthys W, van Goozen SH, Snoek H, van Engeland H. Response perseveration and
sensitivity to reward and punishment in boys with oppositional defiant
disorder. Eur Child Adolesc Psychiatry 2004 13(6):362-4.

Nelson, E. E., Jarcho, J. M., & Guyer, A. E. (2016). Social re-orientation and
brain development: An expanded and updated view. Developmental cognitive
neuroscience, 17, 118-127.

Odgers, C. L., Moffitt, T. E., Broadbent, J. M., Dickson, N., Hancox, R. J.,
Harrington, H., ... & Caspi, A. (2008). Female and male antisocial
trajectories: From childhood origins to adult outcomes. Development and
psychopathology, 20(2), 673-716.

Pavlov IP. Conditioned reflexes: an investigation of the physiological activity
of the cerebral cortex (translated and edited by Anrep GV). 1927 University
Press, Oxford.

Raine A. The psychopathology of crime: Criminal behaviour as a clinical
disorder. 1993 San Diego, CA, USA: Academic Press, Inc.

Shapiro SK, Quay HC, Hogan AE, Schwartz KP (1988). Response perseveration and
delayed responding in undersocialized aggressive conduct disorder. Journal of
Abnormal Psychology 1988 97: 371-373.

Somma, A., Andershed, H., Borroni, S., Salekin, R. T., & Fossati, A. (2018).
Psychopathic Personality Traits in Relation to Self-report Delinquency in
Adolescence: Should We Mind About Interaction Effects? Journal of
Psychopathology and Behavioral Assessment, 1-10.

Van Domburgh L, Vermeiren R, Blokland AA, Doreleijers TA. Delinquent
Development in Dutch Childhood Arrestees: Developmental Trajectories, Risk
Factors and Co-morbidity with Adverse Outcomes during Adolescence. J Abnorm
Child Psychol 2009 37(1):93-105.

The primary objective is to investigate brain functioning during fear
conditioning and reward/punishment conditions in relation to persistent and
desistent DBD patterns by means of functional magnetic resonance imaging
(fMRI), in a large cohort of adolescents with a history of police contacts
below the age of twelve, who have previously been diagnosed with early-onset
DBD (DBD-p versus DBD-d) or had subclinical levels of DBD. Secondary objectives
include investigation of connectivity between brain structures known to be
involved in fear conditioning and reward and punishment through Diffusion
Tensor Imaging (DTI) techniques (e.g. amygdala and ventromedial prefrontal
cortex) and their structure through structural MRI.

The main objective of the genetic follow-up (*Amendement genetica*) is to test
whether functional gene sets are related to putative brain endophenotypes
(structure, connectivity) of antisocial behaviour in our juvenile delinquent
sample. We aim to identify biological pathways underlying antisocial behaviour,
which could inform and improve current treatment strategies.

The main objective of the fifth follow-up ('Amendement wave 5') is to test
which underlying mechanisms can explain why some people persist in showing
antisocial behavior, while others do not. Here we investigate three candidate
mechanisms and their neurobiological basis: self-concept, (social) reward
learning and impulse control. Secondary objectives include behavioral
assessment of affective control, social learning of anxiety and moral learning.

Amendment "EEG / Justice" has the same main aim as "Amendment Wave 5". The
inclusion of judicial / police data is essential to be able to classify the two
groups not only by self-report but also by official registration reports. EEG
recording to the moral learning task gives a unique opportunity to examine the
temporal neural correlates and spatial neural correlates of the moral learning
to the social reward task that is already included in Wave 5.

This study is a non-therapeutic observational cross-sectional study. It
concerns the fourth wave of an ongoing longitudinal project (Van Domburgh et al
2009).

Within the genetic follow-up DNA will be collected from 250 individuals who
have previously participated in our longitudinal study. The participants are
informed in writing about the study and asked whether they wish to participate.
Once the informed consent document has been signed, the saliva collection will
take place during a home visit. During this visit, the participants provide a
saliva sample using a non-invasive saliva sampling kit. Genetic analysis
experiments require the genomic DNA from the study sample to be of adequate
quantity and quality. Therefore, when employing saliva sampling to obtain DNA,
we will encourage all study participants to provide sufficient sample (2,5 mL)
to minimize potential loss of data during downstream genotyping. The spit
sample will be analyzed on a DNA microarray testing for specific
single-nucleotide polymorphisms (SNPs). These SNPs represent the variation in
the human genome and are further examined in a genetic association analysis in
which we make use of a recently developed gene-network approach. Through this
approach we expect to identify functional groups of genes that are associated
with a reduced function, structure and connectivity of the brain regions that
play a role in antisocial behaviour. Moreover, the obtained saliva - under the
condition of funding - could be used to investigate whether certain
environmental factors in childhood, such as child abuse, can bring about
changes in the human epigenome. Such epigenetic design could help us to
ascertain whether negative environmental factors via epigenetic modifications
can lead to an increased risk of antisocial behavior. Additionally, the
participants will be asked/measured on their general biometric/physiological
characteristics (height, weight, skinfold, digit ratio and hip-to-waist ratio)
and the MINI-International Neuropsychiatric Interview will be employed to asses
the diagnosis of antisocial personality disorder (ASPD) The MINI is a brief
structured diagnostic psychiatric interview for dsm-iv en icd-10 psychiatric
disorders and the administration time of the antisocial personality disorder
section will be approximately 5 minutes. In accordance with the diagnostic
criteria for the fifth edition of the Diagnostic and Statistical Manual of
Mental Disorders (DSM-5), we will complement the short MINI interview with a
small number of items to achieve full diagnostic assessment of ASPD as well as
two items on smoking behavior. We will include the specifier *With Significant
Callous-Unemotional Traits* to the diagnosis of Conduct Disorder that can be
used in combination with the existing subtypes measured in our previous waves.
This specifier consists of only 4 items and measures the presence of
callous-unemotional traits. We expect that the questionnaires will take no more
than 30 minutes to complete in total.

The fìffh wave(*Amendement Wave 5*) is also a non-therapeutic observational
study. The fith wave is a follow-up to the fourth wave after 7-B years. This
fifth
wave involves re-assessmenl of behavioral, neuropsychological and structural
MRI measures from wave 4. Hcwever, the fMRI part differs from the fourth wave
in that other tasks will be performed in the scanner: a self-concept task,
vicarious reward leaming task and impulse control task. Next, on a behavior
level, we investigate affective control, vicarious fear learning, and moral
learning. In addition, we will also collect saliva samples for hormone
measurements. All measurements are non-invasive

The 'EEG / Justice' amendment adds to the Wave 5 protocol a questionnaire on
cyber crime, requesting justice / police data, and EEG recording (68 channel)
under the moral learning task.

Van Domburgh L, Vermeiren R, Blokland AA, Doreleijers TA. Delinquent
Development in Dutch Childhood Arrestees: Developmental Trajectories, Risk
Factors and Co-morbidity with Adverse Outcomes during Adolescence. J Abnorm
Child Psychol 2009 37(1):93-105.

Non-therapeutic observational study: Although no direct benefit is to be
expected for participants, this study aims at increasing insight into the
mechanisms driving the pathogenesis and persistence versus desistence of
early-onset DBD.

The burden of *Amendement genetica* is minimal compared to the MRI study.

The burden, benefits and risks of 'Amendement Wave 5' is comparable to the MRI
study (wave 4). The MRI procedure is extended by 10 minutes (resulting in a
load of 60 minutes). Participants are now young adults and are expected to be
able to perform tasks during a slightly longer period of time.

'EEG / Justice amendment': For the addition to the fifth measurement, the
benefits and risks will be comparable to those of the fourth / fifth
measurement. EEG recording (68 channel) will now be added to the moral learning
task, which takes ~40 minutes extra time.