Regulating violence: response inhibition is
differentially related to instrumental and reactive
aggression
Kevin Kemkes, 3542998
August 24, 2014
Writing assignment
Neuroscience and Cognition Master Program, Utrecht University
Conducted at:
Helmholtz Institute
Department of Experimental Psychology
Utrecht University, The Netherlands
Word count: 6033
References: 47
Supervisor/primary assessor:
David Terburg, PhD.
Assistant Professor
Helmholtz Institute, Utrecht University
Secondary assessor:
Prof. Jack van Honk
Professor of Social Neuroscience
Helmholtz Institute, Utrecht University
Honorary Professor, University of Cape Town
Abstract
Response inhibition is the termination or prevention of impulsive motor responses. Impaired
response inhibition has been primarily related to disorders with pronounced impulsivity. The current
review proposes that response inhibition performance is also central to the symptomatology of
aggressive disorders. Importantly, it is proposed that response inhibition performance is related to
increased instrumental aggression (or goal-directed aggression), but decreased reactive aggression
(or aggression in response to frustration/threat). This is because response inhibition is implicated in
emotional and behavioral regulation. Reactive aggression is related to impaired emotional and
behavioral regulation, while instrumental aggression requires strong emotional and behavioral
regulation.
The purpose of this review is to explore this hypothesis by focusing on the relationship of
response inhibition with disorders related to of impulsivity and aggression. Strong evidence in favor
of the hypothesized relationship will be presented by focusing on studies showing that aggressive
disorders hallmarked by instrumental aggression are related to improved response inhibition, while
disorders with pronounced reactive aggression are related to impaired response inhibition.
Furthermore, the current review aims to explore possible neurobiological mechanisms
underlying this relationship. Recently the dual-hormone serotonergic (DHS) hypothesis of aggression
has been proposed. This states that high testosterone/cortisol ratios predispose to increased general
aggression, after which 5-HT (or serotonin) levels affect the balance between instrumental and
reactive aggression by mediating impulsivity. The current review will propose that response
inhibition mediates the relationship of 5-HT with instrumental and reactive aggression.
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1. Introduction
Aggressive behavior is a big concern for society because of the devastating consequences for both
the aggressor and the victim. In addition, aggressive behaviors form a serious economic burden. In
The Netherlands, the annual costs of intimate partner violence alone is already estimated around
142.2 million US dollars (World Health Organization, 2004). This burden is larger at the extremities of
violent behavior such as aggressive disorders. For example, the overall prevalence of psychopathic
personality traits associated with increased violent behavior are commonly estimated around 1% of
the general population (for example Neumann & Hare, 2008), while the prevalence of psychopathic
traits in the Dutch prison population has been estimated around 21.7% (Hildebrand, de Ruiter, &
Nijman, 2008). It is therefore important to study how the nervous system is implicated in aggressive
behaviors since this could lead to new strategies to prevent aggressive behaviors from occurring.
1.1 Aggression and impulsivity
Aggression disorders are often accompanied by increased impulsivity, and disorders with
pronounced impulsiveness are often accompanied by increased aggression (Hart & Dempster, 1997;
Retz & Rösler, 2010; Wallcott, Mangione & Landau, 2004). This suggests that a relationship exists
between levels of impulsivity and aggression. However, aggression and impulsiveness are very
heterogeneous concepts, and it is currently unclear how different forms of aggression are related to
the neurobiological and cognitive mechanisms underlying impulsivity.
Aggression is an overt behavior that is intended to inflict physical damage on another
individual (Nelson & Trainor, 2007). Researchers have found two well-validated dimensions of
aggressive behavior. Reactive aggression is performed in response to frustration/threat, whereas
instrumental aggression is performed to achieve goals (Blair, 2001).
Impulsivity has been defined as a personality trait associated with risk-taking, lack of
planning, and making up one’s mind quickly (Arce & Santisteban, 2006). Experimental psychologists
distinguish between motor impulsiveness and cognitive impulsiveness (Bechara, Damasio & Damasio,
2000). The former is similar to (and hereafter will be referred to as) response inhibition, whereas the
latter is related to the capacity to delay gratification. Response inhibition can be described as the
termination or prevention of impulsive motor responses.
In line with this distinction of cognitive and motor impulsivity, lesion and functional magnetic
resonance imaging (fMRI) studies show that response inhibition is more related to the dorsolateral
prefrontal cortex (DLPFC), whereas cognitive impulsiveness is related to the ventromedial prefrontal
cortex (VMPFC; Bechara, Damasio & Damasio, 2000).
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The motor tasks most often used to test response inhibition performance are the stop-signal
task and the Go/NoGo task (Swick, Ashley, & Turken, 2011). The stop signal task involves a simple
choice-reaction time task, in which the primary task is followed by a stop signal during a proportion
of trials. The delay between primary task and stop signal (or the stop signal delay; SSD) is altered to
find the latency at which the participant can inhibit responses in 50% of the stop trials. The Go/NoGo
task involves a discrimination task in which the participants should respond to certain, but not to
other stimuli. Difficulty is altered by the proportion of NoGo stimuli. The former task involves
terminating an ongoing response process, whereas the latter involves the prevention of a response
process.
The current review will focus on the relationship between response inhibition, but not
cognitive impulsiveness, with instrumental and reactive aggressive behavior for the following
reasons. First, Dougherty, Bjork, Harper, el al. (2003) found that computer tasks designed to assess
response inhibition are more sensitive for discrimination between groups with and without
disruptive behaviors then those that asses cognitive impulsivity. This suggests that response
inhibition task performance reflects regulatory deficits in aggressive populations more uniquely then
cognitive inhibition tasks.
Second, Feilhauer, Cima, Korebrits, and Kunert (2012) demonstrated in a sample of subjects
with conduct disorder that response inhibition performance is positively correlated to self-reported
reactive aggression, while being negatively correlated to instrumental aggression. This shows that
response inhibition performance can discriminate between the two dimensions of aggressive
behavior. Reactive aggression, with its uncontrolled and explosive nature, is related to impaired
response inhibition. Instrumental aggression, with its callous and goal-directed nature, is related to
improved response inhibition.
Last, response inhibition is a mechanism implicated in emotion-regulation. For example, a
study by Walcott, Mangione, and Landau (2004) showed that emotion regulation during a frustrating
peer competition is related to response inhibition performance. In this study, an ADHD and healthy
group were instructed to either regulate or not to regulate their emotions during the competition.
Response inhibition was impaired after the competition when healthy participants were not required
to regulate emotions. The ADHD group showed an overall lack of emotional regulation and repsonse
inhibition. Response inhibition is a mechanism used n emotion-regulation important to delay
impulsive behavioral responses. This allows a person consider social consequences of intended
behaviors.
For these reasons, the current review will explore the hypothesis that response inhibition
performance is related to increased instrumental and decreased reactive aggression. In the
conceptualization of this review the neural mechanisms of response inhibition are required to
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regulate emotion and behavior. Instrumental aggression requires strong regulation of emotion and
behavior, whereas a tendency to reactive aggression is caused by impaired regulation.
If it is the case that response inhibition can differentiate between instrumental and reactive
aggression, then response inhibition performance could potentially be measured to personalize
medicine and predict treatment outcome. Another important question that will be addressed is
which neurobiological mechanisms could underlie the relation of response inhibition with reactive
and instrumental aggression. Since much is known about the neurobiology of response inhibition and
aggressive behavior, relating response inhibition to instrumental and reactive aggressive behavior
could lead to new insights.
First, the relationship of response inhibition with reactive and instrumental aggression in
mental disorders will be discussed to explore the hypothesis on a behavioral level. This will be
followed by a review of the neurobiology underlying response inhibition, reactive aggression and
instrumental aggression. There will be a special focus on the Dual-Hormone Serotonergic (DHS)
hypothesis that has been proposed by Montoya, Terburg, Bos, and van Honk (2012).
2. Disorders of aggression and impulsivity
Traditionally, researchers interested in response inhibition have focused on inhibitory deficits in
ADHD. However, response inhibition also seems to be a central component in disorders with
pronounced instrumental and reactive aggression. The hypothesis stated above predicts that
disorders with clear distortions in impulsivity are related to increased reactive aggression and
reduced instrumental aggression. It also predicts that aggression disorders hallmarked by
instrumental aggression are related to improved response inhibition, and those disorders related to
reactive aggression are related to impaired response inhibition.
2.1 Attention-deficit/hyperactivity disorder
ADHD is characterized by deficits in executive functions resulting in increased impulsive behavior
(Walcott, Mangione & Landau, 2004). ADHD is strongly associated with impaired response inhibition.
A study by Retz & Rösler (2010) investigated the prevalence of reactive and instrumental violent
offenses in a forensic sample of adult men. In this sample ADHD and childhood ADHD traits were
diagnosed by trained psychiatrists. Participants were placed either in a no-ADHD, ADHD (partially
remitted) or ADHD group. Childhood ADHD symptoms were scored by use of a self-report
questionnaire. In addition, another group of researchers rated the criminal offenses conducted by
the offenders on reactive and instrumental aggressive components.
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The results by Retz & Rösler (2010) show that the offenses committed by the ADHD group
scored higher on reactive aggression then the ADHD (partially remitted) group, which in turn scored
higher than the no-ADHD group. In addition, the offenses by the no-ADHD group showed increased
instrumental aggression compared to the other groups. The self-report data showed that childhood
ADHD symptoms had a positive relationship with reactive aggression, but a negative relationship
with instrumental aggression.
2.2 conduct disorder
Conduct disorder (CD) is a childhood disorder that features a “repetitive and persistent pattern of
behavior in which the basic rights of others and major age-appropriate societal norms or rules are
violated” (Loeber, Burke, Lahey, Winters, & Zera, 2000, p. 1469) and could be considered as a child
form of antisocial disorder (Blair, 2001). Conduct disorder is often comorbid with ADHD, but is also
independently diagnosed. Compared to psychopathy it is hallmarked by increased reactive
aggression and decreased instrumental aggression (Feilhauer, Cima, Korebrits, & Kunert, 2012),
although both behaviors can be present.
The study by Loeber et al. (2002) investigated response inhibition in children with ADHD,
ADHD with conduct disorder, conduct disorder, no disorder and anxiety disorders (the latter will not
be discussed). They aimed to investigate if response inhibition was a core feature of conduct
disorder, or if this was due to its comorbidity with ADHD. Loeber et al. (2002). found that the ADHD,
CD and combined group showed response inhibition impairments compared to the control group.
Furthermore, no distinction could be made between the three disorder groups based on response
inhibition performance. Thus, this disorder that is often associated with increased reactive
aggression is related to impaired response inhibition.
Conduct disorder, however, is a very heterogeneous concept, and a subset of patients with
this disorder shows increased instrumental aggression. The study by Loeber et al. (2002) did not
account for this heterogeneity. A study by Bennett, Pitale, Vora, & Rheingold (2004) sheds more light
on the relationship between childhood antisocial behaviors and the dimensions of aggression. Note
however that this study measured antisocial traits in a non-clinical sample.
Bennett et al. (2004) divided antisocial traits in reactive and proactive antisocial dimensions.
Reactive and instrumental aggression were included in the former and latter concepts, respectively.
The study by Bennett et al. (2004) showed that reactive antisocial traits are more related to
measurements of ADHD traits then proactive antisocial traits. However, proactive antisocial traits
also correlated with ADHD traits in adolescents and higher age groups (in a weaker but positive
relationship, in contrary to the hypothesis of the current review). As the authors pointed out, this is
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in line with the earlier onset of reactive versus proactive traits in the development of antisocial
behavior.
This study is relevant for several reasons. First, response inhibition deficits are central to
ADHD traits. Second, reactive aggression is a core feature of reactive antisocial traits and
instrumental aggression is a core feature of proactive antisocial traits. Thus, the study by Bennett et
al. (2004) shows that increased impulsive traits are more strongly related to antisocial behavior that
includes reactive aggression then to antisocial behavior that includes instrumental aggression.
However, it is important to note that levels of aggressive behavior were not assessed directly.
2.3 antisocial personality disorder
A diagnosis for an antisocial personality disorder has similar behavioral criteria as conduct disorder,
except that it is diagnosed in adults (Loeber et al, 2000). A study by Dolan & Park (2002) investigated
whether patients with a diagnosis for an antisocial personality disorder show deficits in
neuropsychological tasks related to the VMPFC and DLPFC. As mentioned, emotion regulation has
been related to both of these areas. These VMPFC-related tasks included a Go/NoGo task to measure
response inhibition. The study by Dolan & Park (2002) was inspired by inconsistencies in the
literature about whether antisocial personality disorder is related to VMPFC damage or also to DLPFC
damage. Patients showed impaired performance on VMPFC-related and DLPFC-related tasks. The
authors therefore suggested that antisocial personality disorder is associated with dysfunction of
both the VMPFC and DLPFC.
This data is in line with the above mentioned study by Loeber et al. (2002). Those authors
reported essentially the same general impairment of response inhibition in CD patients. Thus, both
conduct disorder and antisocial disorder are in general associated with decreased response
inhibition. Both CD and antisocial personality disorder are more associated with reactive aggression,
and less associated with instrumental aggression, then psychopathy. Similar to Loeber et al. (2012),
an important limitation of the study by Dolan & Park (2002) is that the authors did not differentiate
between those patients expressing instrumental and reactive aggression.
2.4 Psychopathy
Psychopathy is a developmental disorder hallmarked by affective and behavioral components like a
lack of empathy and increased violent and criminal behavior (Blair, 2010b; Feilhauer, et al., 2012).
Psychopathic behavior can be described by two dimensions, the affective-interpersonal and the
antisocial dimension. The former is traditionally characterized by manipulation and instrumental
aggression, whereas the latter is characterized by impulsivity and reactive aggression (Feilhauer et
al., 2012). The antisocial dimension also highly overlaps with antisocial disorders. The primary
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distinction between psychopathy and antisocial personality disorder is often in the severity of
affective-interpersonal traits.
The study by Feilhauer et al. (2012) investigated the validity of this dual model for
psychopathy by assessing psychopathic traits in both healthy participants and those diagnosed with
conduct disorder. They related self-reported instrumental and reactive aggression to response
inhibition. In addition Feilhauer et al. (2012) also related psychopathic traits in these samples to
reactive and instrumental aggression. Importantly, their study clearly demonstrates that response
inhibition performance is positively related to self-reported instrumental aggression but negatively
related to self-reported reactive aggression. Their results also show that the antisocial psychopathic
dimension is associated with increased reactive aggression. No relationship was found for the
affective-interpersonal dimension and response inhibition. The study by Feilhauer et al. (2012) is the
most convincing evidence that shows the existence of the hypothesized relation of response
inhibition performance with reactive and instrumental aggression to date.
3. The prefrontal cortex
The previous section showed that response inhibition performance is negatively related to reactive
aggression but positively related to instrumental aggression in impulsive and aggressive disorders. In
order to understand the link between response inhibition and aggression one needs to understand
the underlying neurobiology. Response inhibition and emotional regulation are both related to the
prefrontal cortex (Nelson & Trainor, 2007; Aron, Fletcher, Bullmore, Sahakian, & Robbins, 2003). It
thus seems logical to expect an interplay between response inhibition and aggression regulation in
this region of the brain.
3.1 Role of prefrontal areas in aggression and response inhibition
Especially the DLPFC and VMPFC play a key role in emotion regulation (Blair, 2010a; Perach-Barzilay,
Tauber, Klein, et al. 2013). Frontal areas regulate aggressive behavior with their inhibitory input into
subcortical structures that are involved in aggression (Nelson & Trainor, 2007). In line with this, low
baseline activity in the prefrontal cortex has been associated with increased reactive aggression
(Volkow, Tancredi, Grant, Gillespie, Valentine, Mullani, Wang, & Hollister, 1995). Several studies
suggest that prefrontal regulation of aggression depends on 5-HT input (for a review see Montoya et
al. 2012). Since these receptors receive input from the 5-HT raphe system that originates in the
brainstem (Lesch & Merschdorf, 2000), this shows that the relationship between cortical and
subcortical areas is not simply characterized by top-down control, but that the cortex also receives
bottom-up connections. Increased instrumental aggression has been related to increased activation
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of the DLPFC during emotion-processing tasks (Glenn & Raine, 2009). This suggests that instrumental
aggression relates to enhanced cognitive control in order to guide emotional processing.
The DLPFC also seems to play an important role in response inhibition (Aron et al., 2003). The
DLPFC, as a functional area, is located on the inferior frontal gyrus (rIFG). The study by Aron et al.
(2003) found that rIFG lesions often result in the impairment of response inhibition. Moreover, they
found that the lesion size is correlated to response inhibition impairment. This relationship was not
found for the left IFG or other brain areas. These studies provide strong evidence for a rightlateralized response inhibition network of the human brain. This finding has been replicated by using
transcranial magnetic stimulation, in which inhibiting rIFG activity resulted in impaired response
inhibition performance (Chambers, Bellgrove, Stokes et al., 2006).
FMRI studies confirm the right-lateralized inhibition network for response inhibition (Dillon &
Pizzagalli, 2013). These studies show that the DLPFC is a key regulator, supplemented by the frontalparietal cortex, anterior cingulate cortex (for an extensive overview see Garavan, Hester, Murphy,
Fassbender, & Kelly, 2006; Aron, 2003). After receiving information about the presence of a stop
signal, these areas work in concert to suppress activity in the motor areas via suppression of basal
ganglia output.
This last finding is very important because the proposed function of the DLPFC in response
inhibition and emotion regulation shows important overlap. During response inhibition, the DLPFC is
thought to inhibit basal ganglia output (Aron, 2011), whereas in emotion regulation it inhibits
subcortical areas related to anger and aggression (Blair, 2010a; Perach-Barzilay, et al. 2013). This
overlap is consistent with the view that response inhibition mechanisms are required for the
regulation of aggressive behaviors.
4. The role of subcortical structures in aggression and response inhibition
Aggressive responses rely on an evolutionary old system composed of subcortical structures that
drive aggressive behavior (Panksepp, 1998, p. 196). In contrast to aggression, much less is known
about the influence of subcortical structures on response inhibition performance. This section will
describe how the amygdala and hypothalamus are related to aggressive behavior and will mention
some interesting findings on their relation to response inhibition.
4.1. Role of the amygdala in aggression and response inhibition
The amygdala receives sensory input and is implicated in both dimensions of aggressive behavior
(Blair, 2010a). It functions to detect emotionally salient stimuli. Based on this information it mediates
activity in other subcortical structures including the hypothalamus (Panksepp, 1998, p.196). The
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amygdala is also interconnected with the prefrontal cortex (Banks, Eddy, Angstadt, Nathan, & Phan;
2007). The coupling of the amygdala with the prefrontal cortex is of major importance for emotion
regulation (Banks et al. 2007). That is, stronger covariation of neural activity between the amygdala
and prefrontal cortex is related to improved regulation of negative affect. These prefrontal areas
include the DLPFC that is also related to response inhibition.
In subjects demonstrating high reactive aggression the amygdala response caused by threat
stimuli is increased (Coccaro, McCloskey, Fitzgerald, & Phan, 2007). This probably results in overinterpretation of ambiguous and threat stimuli, thereby increasing reactive aggressive behavior.
Psychopathic traits like instrumental aggression have been associated with reduced amygdala
responses to a variety of tasks that involve emotional learning and emotional processing (Blair,
2010b). This is in line with impairments in recognizing distress in other individuals. Thus amygdala
reactivity seems to be suppressed in patients with pronounced instrumental aggression but
enhanced in patients with pronounced reactive aggression.
There are not many studies regarding the role of the amygdala in response inhibition.
Increased amygdala activity has been related to improved response inhibition in an emotional
Go/NoGo task (Pawliczek, Derntl, Kellermann, Kohn, Gur, & Habel, 2013). In this task, participants
with high trait aggression showed reduced response inhibition. Also, participants showed relative
improvement of response inhibition when the stop stimulus was an angry facial expression compared
to a neutral expression. In addition to the cortical response inhibition network, the angry stop
stimulus was related to increased right amygdala activity (amongst others).
According to Pawliczek et al. (2013) the amygdala, due to its extensive connections with the
cortex, enhances the processing of the stop signal when it contains a threat stimulus. This results in
improved response inhibition performance. One argument in favor of this view is that Pawliczek et al.
(2013) also found increased activity in the occipital lobe found during angry stop signals compared to
neutral stop trials.
4.2 Role of hypothalamus in aggression and response inhibition
The hypothalamus receives major input from the amygdala (Panksepp, 1998, p.196). In addition, the
hypothalamus is part of, and receives information from, the endocrine system (discussed below).
This is where physiological “irritations” that dependent on the endocrine system, like hunger, can
influence aggressive behavior. The hypothalamus regulates the endocrine and autonomic nervous
system.
Animal studies show that reactive aggression is mainly associated with the medial
hypothalamus, whereas the lateral hypothalamus is implicated in predatory aggression (Siegel &
Victoroff, 2009). Predatory aggression is often used as a model for human instrumental aggression. It
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shows some superficial characteristics similar to instrumental aggression such as a goal-directed and
callous nature. Predatory aggression, however, is not homologous to human instrumental aggression
and one should be careful with generalizations.
The hypothalamus relays signals to the periaqueductal grey (PAG), which has extensive
reciprocal connections with the frontal cortex and other areas of the brain (Panksepp, 1998, p. 197).
Together, the amygdala, hypothalamus and PAG together form a well-known reactive aggression
network that causally induces reactive aggressive behavior in animals when stimulated. To the
authors best knowledge no study has directly associated the hypothalamus activity or lesions with
response inhibition. However, the hypothalamus is a key regulator of the endocrine system. Later,
some interesting evidence for hormonal influence on response inhibition will be discussed.
5. The role of 5-HT, cortisol and testosterone in aggression and response inhibition
Studying role of hormones and 5-HT in aggression and response inhibition is very important since
they are potential targets of pharmacological treatments. 5-HT is a major modulator of aggressive
behavior (Lesch, 2000, Nelson & Trainor, 2007). Furthermore, 5-HT is explicitly related to impulsivity
(Clark, Roiser, Cools, Rubinsztein, Sahakian, & Robbins, 2005), which makes it a likely candidate for
mediating the hypothesized relation of response inhibition with increased instrumental and
decreased reactive aggression. Testosterone has been known to regulate social aggression in animals
(for example Wingfield et al. 1990) including humans (Bos, Panksepp, Bluthé, & van Honk. 2012). The
effect of testosterone and 5-HT on aggression might depend on low levels of cortisol (Montaya et al.
2012). This section will explore how these hormones and 5-HT are related to reactive aggression,
instrumental aggression and response inhibition.
5.1 The role of testosterone/cortisol ratios in aggression
Testosterone is an androgen steroid hormone that is regulated by the hypothalamic-pituitarygonadal (HPG) axis. Testosterone promotes aggression by increasing reactivity on social challenges
(referred to as the “challenge hypothesis”, see Wingfield et al., 1990; Bos et al., 2012). It should be
noted, however, that dealing with social challenges can be achieved by other means then aggression.
Some challenges will result in aggressive behavior, and therefore the total number of aggressive
behaviors increase with high levels of testosterone.
In line with this view, research clearly shows a relationship between testosterone levels and
aggressive behavior (Pavlov, Chistiakov & Chekhonin, 2012; Montoya et al., 2012; Bos et al. 2012).
For example, testosterone increases hearth rate responses specifically after seeing angry facial
expressions (van Honk, Tuiten, Hermans et al., 2001) This could be interpreted as an enhanced
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disposition to defend social status. In addition, testosterone increases amygdala, hypothalamus and
rIFG activation in response to emotional faces compared to neutral faces, especially for angry facial
expressions (Hermans, Ramsey, & van Honk, 2008). Thus, testosterone improves the responsiveness
of structures related to aggression and aggression regulation. This is in line with the idea that
testosterone enhances the readiness to fight by increased threat perception (Bos et al., 2012).
The relationship of testosterone with aggression depends strongly on the interaction of
testosterone with cortisol. Cortisol is a steroid hormone released by the adrenal gland and regulated
by the hypothalamus-pituitary-adrenal (HPA) axis (Montoya et al. 2012). It is the primary stress
hormone. The effect of testosterone on aggression is more pronounced under low basal levels of
cortisol (for a review see Montoya et al., 2012). Low basal levels of cortisol are related to low fear
and therefore can promote aggressive behavior.
High testosterone/cortisol ratios decrease the communication between cortical and
subcortical areas (Terburg, Morgan & van Honk, 2009). Due to enhanced subcortical activity in the
amygdala high testosterone/cortisol ratios promote reactive aggressive behaviors. Likewise, this
decoupling results in “emotionally cold” instrumental aggression since the cortex does not receive
input from limbic structures. These findings resulted in the hypothesis that high testosterone/cortisol
ratios are related to both increased reactive and instrumental aggressive behavior. These
relationships have been confirmed in several clinical populations including conduct disorder and
psychopathy (see Montoya et al. 2012).
There is a clear lack of studies regarding the effect of testosterone and cortisol on response
inhibition. There is a single but interesting study that has been done in relation to anti-androgen
therapy in men, which is a common treatment for prostate cancer (Chao, Uchio, Zhang, Hu, Benarski,
Luo, Rose, Concato, & Li, 2012). Note that an anti-androgen treatment does not only target
testosterone. However, antagonizing receptors for testosterone on cancer cells to reduce stimulation
of cell division is a primary treatment goal.
By using fMRI, the study by Chao et al. (2012) found that androgen depletion decreased the
BOLD response in the MPFC, right insula, and importantly the middle/inferior frontal cortex during a
stop signal task. These frontal areas are implicated in emotion-regulation. This study shows that
response inhibition networks can be modulated by hormone levels. Future studies should aim to
investigate the effect of testosterone, cortisol and testosterone/cortisol ratios on response
inhibition.
5.2 Role of 5-HT in aggression and impulsivity
The 5-HT system specifically mediates reactive aggression. The effects of 5-HT on aggression are
mainly mediated by the 5-HT raphe system in the brain stem (Lesch & Merschdorf, 2000; Siegel &
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Victoroff, 2009). This system projects from the raphe nucleus to a large amount of brain areas
including the amygdala, hypothalamus and the areas in the frontal cortex Low baseline levels of 5-HT
are associated increased reactive aggressive behaviors in men and rodents (Nelson & Trainor, 2007;
Montoya, 2012). This is supported by human studies, in which reactive aggressive behavior was
inversely related to 5-HT1A receptor binding potential (Parsey, Oquendo, Simpson, Ogden, van
Heertum, Arango, & Mann (2002).
The relationship between 5-HT and instrumental aggression is unclear for humans. In
addition, animal studies on the relation of 5-HT and predatory behavior show mixed results. Some
animal studies regarding predatory aggression in rodents show that administering 5-HT affects
reactive aggression but not predatory aggression (Ferrari, Palanza, Rodgers, Mainardi, & Parmigiani,
1996). However, a review by Nikulina (1991) showed that psychopharmacological treatments that
increase 5-HT level inhibits predatory behavior in several kinds of animals. Thus, the relationship of
5-HT with predatory aggression in animals and instrumental aggression in humans remains unclear.
Increasing 5-HT results in increased glucose metabolism in the orbitofrontal cortex, cingulate
cortex and VMPFC in healthy subjects (Siever, Buchsbaum, New, et al., 1999). However, this effect
was not found for reactive aggressive patients. This finding is in line with the view that 5-HT increases
activity in frontal areas related to emotion-regulation and that reactive aggressive patients lack
cortical regulation of aggression.
The findings on testosterone/cortisol ratios and 5-HT have led to the DHS hypothesis
(Montoya et al. 2012). This hypothesis states that high basal testosterone/cortisol ratios predispose
towards general aggression, while 5-HT levels affect the balance between instrumental and reactive
aggression. Low prefrontal 5-HT predisposes to reactive aggression by increasing impulsivity, while
high prefrontal 5-HT levels predispose to instrumental aggression by reducing impulsivity.
The notion that 5-HT influences the balance between instrumental and reactive aggression
due its relation to impulsivity is very important. This is because response inhibition is also strongly
related to impulsivity (Arce & Santisteban, 2006). Because of the hypothesized relation of 5-HT with
reactive and instrumental aggression, the hypothesis outlined at the start of this review would
predict a positive relation between 5-HT and response inhibition. There is evidence that neural motor
inhibition networks are effected by 5-HT levels. A study by Rubia, Lee, Cleare, Tunstall, Fu, Brammer
& McGuire (2005) showed a reduction of activity in the rIFG after tryptophan depletion during motor
inhibition in a Go/NoGo task. Tryptophan is a precursor of 5-HT, and tryptophan depletion thus
results in low 5-HT levels in the brain. This reduction in rIFG activation shows that low 5-HT levels
impair activity in areas that are strongly implicated in response inhibition.
In another study, Passamonti, Fera, Magariello, et al. (2006) found a similar pattern. They
compared carriers of a low-activity versus high-activity allele of monoamine oxidase-A (MAOA) gene.
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High expression of MAOA genes is associated with lower synaptic serotonin levels. In this study the
right ventrolateral prefrontal cortex showed increased activity during response inhibition in a
Go/NoGo task for subjects with high expression of this gene. This area has been associated with
impulsiveness.
Because of the association of response inhibition with impulsivity and emotion-regulation,
response inhibition might be a mechanism that mediates the relationship of 5-HT with instrumental
and reactive aggression that is proposed by the DHS hypothesis. The findings by Rubia et al. (2005)
and Passamonti et al. (2006) show that lower 5-HT levels are related to lower activity in areas that
have been related to response inhibition and impulsivity. As mentioned above, response inhibition
performance is related to increased instrumental and decreased reactive aggression in disorders of
aggression and impulsivity. These relationships of response inhibition with 5-HT and aggression are in
congruent DHS hypothesis.
6. Conclusion and future directions
The current review investigated the hypothesis that response inhibition is related to increased
instrumental and decreased reactive aggression. This was investigated on a behavioral level by
looking at the relationship of response inhibition with reactive and instrumental aggression in mental
disorders. Further, the relationship of neural mechanisms of response inhibition with reactive
aggression and instrumental aggression have been compared. This led to an extension of the DHS
hypothesis proposed by Montoya et al. (2012).
6.1 conclusions
Studies towards ADHD and aggressive disorders convincingly demonstrate the hypothesized relation
of response inhibition with reactive and instrumental aggression on a behavioral level. Research
towards psychopathic traits in conduct disorder showed that response inhibition is related to
increased instrumental but decreased reactive aggressive behavior. Furthermore, aggressive
disorders that are associated with pronounced reactive aggression are related to impaired response
inhibition. Studies regarding ADHD, a disorder hallmarked by impaired response inhibition, clearly
demonstrate increased reactive and decreased instrumental aggression compared to healthy
subjects.
The VMPFC and DLPFC are important areas for the regulation of aggression. In addition, the
VMPFC is related to cognitive inhibition, whereas the DLPFC is important for response inhibition. The
DLPFC has inhibitory inputs into subcortical structures involved in aggressive behavior and the basal
ganglia involved in motor activity. Instrumental aggression requires strong prefrontal regulation of
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emotion and behavior as it is callous and goal-directed. Reactive aggression can be the result of
impaired prefrontal regulation of emotion and behavior, resulting in increased aggressive drive. In
line with this, individuals with pronounced instrumental aggression show reduced amygdala activity
but increased DLPFC activity during emotional processing tasks. Furthermore, reactive aggression is
related to increased amygdala activity in response to threat stimuli but reduced baseline prefrontal
activity.
The DHS hypothesis states that the balance between instrumental and reactive aggression is
mediated by 5-HT under high testosterone/cortisol ratios. 5-HT is strongly associated with
impulsivity, which in turn is associated with impaired response inhibition. The 5-HT raphe nucleus
projects to major cortical and subcortical areas implicated in emotional and behavioral regulation. It
has been shown that low 5-HT levels are related to increased reactive aggression. Furthermore,
increasing 5-HT levels results in increased activity of prefrontal areas related to emotional and
behavioral regulation. In addition, reducing 5-HT by tryptophan depletion reduces activity in the rIFG
during response inhibition tasks. This area is of major importance for response inhibition. These
findings demonstrate that the 5-HT raphe system is a neurobiological mechanism that affects the
neural response inhibition networks.
Based on these findings, the current review extends the DHS hypothesis by proposing that
the effect of 5-HT on instrumental and reactive aggression under high testosterone/cortisol ratios is
mediated by response inhibition mechanisms (see figure 1). Low 5-HT levels, strongly related to
impulsivity, result in decreased activity in the IFG (which overlaps with the DLPFC). This explains the
negative association between impulsivity and response inhibition. Response inhibition is implicated
in emotion-regulation. The current model predicts that It is positively related to instrumental
aggression, but negatively related to reactive aggression. This is because the DLPFC regulates activity
in subcortical areas related to aggression, such as the amygdala. Decreased regulation results in
increased subcortical aggressive drive, resulting in increased reactive aggression. On the other hand,
strong cortical regulation results in increased callous and goal-directed instrumental aggression.
15
Figure 1. Proposed model for the relations between trait impulsivity, response inhibition, reactive
aggression and instrumental aggression under high testosterone/cortisol ratios. Behavioral
phenomena are depicted in bold, neural mechanisms in italic. Positive associations are depicted by
continuous lines while negative associations are depicted by dashed lines. The grey lines show
relations predicted by the DHS hypothesis. The black lines represent the additional associations
proposed in this review. In addition to the DHS hypothesis it is proposed that high impulsivity and
low 5-HT activity are related to reduced response inhibition performance and DLPFC activity during
response inhibition. Response inhibition performance is positively related to instrumental aggression
and negatively related to reactive aggression. Instrumental aggression, because of its goal-directed
nature, requires strong cortical control for emotional and behavioral regulation. Reduced prefrontal
regulation results in enhanced aggressive drive to threats and provocations, increasing reactive
aggression
6.2 Future directions
Future studies should elucidate on the neural mechanisms underlying the relationship of response
inhibition with reactive and instrumental aggression. Most importantly, they should aim to study the
influence of hormones on response inhibition. In order to validate the proposed model it is of
primary importance to investigate if response inhibition is more positively related to instrumental
aggression and more negatively to reactive aggression in individuals with high testosterone/cortisol
ratios compared to low testosterone/cortisol ratios. This would be in line with the view that response
inhibition affects the dimension of aggression more strongly in individuals predisposed towards high
general aggression. Elevated testosterone/cortisol ratios seem to occur in a diversity of aggressive
disorders such as conduct disorder and psychopathy (Montoya et al. 2012).
The current review clearly demonstrated a positive relationship between response inhibition
performance and instrumental aggression. However, the relationship of 5-HT with instrumental
16
aggression remains unclear. Although the current review mentioned several studies suggesting a
negative relationship, there is a lack of direct experimental evidence. Reduced 5-HT levels are related
to lower activation in neural response inhibition networks (Rubia et al. 2005; Passamonti et al. 2006)
and increased impulsivity (Clark et al., 2005). Taking these findings into account, the positive
association of instrumental aggression with improved response inhibition suggests a positive
relationship between 5-HT and instrumental aggression. Future studies should directly test this
hypothesis in a single experiment.
The notion that response inhibition is related to increased instrumental and decreased
reactive aggression is highly relevant for clinical treatment and research. Studying response inhibition
in aggressive disorders is especially relevant in the case of psychopathy, since instrumental and
reactive aggression is of primary interest in the distinction between the affective-interpersonal and
the antisocial dimension. The relation of response inhibition with instrumental and aggressive
behavior could be utilized as a predictor of treatment success in aggressive disorders. The current
hypothesis predicts that pharmacological treatments that reduce reactive or instrumental aggression
should be accompanied by an improvement or reduction in response inhibition performance,
respectively. Studying the relationship of response inhibition with instrumental and reactive
aggression could therefore significantly contribute to the well-being of patients and reduce the large
psychological and economical damage caused by aggressive behavior.
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Layman’s abstract
Response inhibition is the capacity to inhibit impulsive responses in reaction-time tasks. It is generally
accepted as a measurement of behavioral control and is inversely related to the personality trait
impulsivity. Response inhibition mechanisms are also important for emotion regulation. Traditionally
response inhibition impairments have been associated with ADHD. The current review proposes that
response inhibition is also central to the symptomatology of aggressive disorders.
Specifically, this reviews shows that response inhibition is differentially related to two major
categories of aggressive behavior. These two categories are reactive and instrumental aggression.
Reactive aggression is aggressive behavior is response to provocation or threat. It has very explosive
nature. Instrumental aggression is performed to achieve goals. It has a goal-directed and callous
nature. This review shows that improved response inhibition is related to increased instrumental
aggression but decreased reactive aggression in several mental disorders. This is because
instrumental aggression requires strong emotional and behavioral regulation while reactive
aggression occurs due to a lack of regulation.
In addition, this review compares the neurobiology of instrumental and reactive aggression
with the neurobiology of response inhibition. A previous model suggested that 5-HT levels, a
chemical used for neural communication, affects the balance between reactive and instrumental
aggression under high hormonal testosterone-to-cortisol ratios. This review shows that low 5-HT
levels also impair the functioning of brain areas important for response inhibition. A model is
proposed in which response inhibition mechanisms mediate the relationship of 5-HT with reactive
and instrumental aggression.
22