Monday, 7 October 2019

The Neuroscience of Psychopathy

A recent BBC drama portrayed a young, psychopathic Russian assassin named ‘Villanelle’ – supposedly derived from the word “villainess”. Based on a series of novels by British author Luke Jennings, the series piqued the interest of viewers, winning numerous awards and breaking records for growth ratings among young adults especially. The shocking yet seductively intriguing character is described as a "chillingly relatable monster"; as charming as she is psychopathic. Displaying an innocent, playful and witty exterior, she is also cold, calculating and callous, having been raised to kill without guilt or concern. While not without its flaws, the character was perhaps one of the most accurate portrayals of psychopathy to grace our screens in recent years, generating a spur of public interest in these haunting yet fascinating individuals. 

Psychopathy commonly refers to a persistent personality disorder in which individuals display extreme antisocial and amoral behaviour along with a complete lack of empathy, an inability to establish meaningful relationships and a failure to learn from experience or social and emotional cues. While psychopaths are impulsive, manipulative and deceitful, they may also be charming, seductive and sometimes highly intelligent, often able to manipulate others through elaborate scams and ruses. Although psychopathy is often associated with amorality – an absence of, or disregard for moral beliefs – the question of whether or not psychopaths know right from wrong has long intrigued researchers. However, studies have largely failed to identify any differences in moral judgment, and it is generally accepted that while psychopaths are well aware of the discrepancy between their behaviour and social or legal expectations, they are unconcerned by this, believing that such expectations do not apply to them. 

From an evolutionary perspective, psychopathy has been described as a “socially parasitic strategy”, which may only exist so long as there is a large population of altruistic and trusting individuals to be exploited. The disorder is known to be strongly hereditary1 and, while psychopaths have a higher risk of death due to violence, risky behaviour and suicide, traits such as promiscuity and adultery offset this to increase reproductive success and thus the passing down of genes thought to predispose children to psychopathy. As with other personality disorders, however, while neurobiological or genetic abnormalities may predispose an individual to developing a psychopathic personality, it is only when combined with certain environmental factors (including poor parental supervision, having a convicted parent or an absent mother, amongst others), that the condition is fully expressed in adulthood. 

While some researchers have proposed that psychopathy may be a learned coping mechanism in which individuals learn to “turn off” emotions in response to traumatic childhood experiences2, there is now firm evidence of specific structural and functional abnormalities in the brains of psychopaths. However, research in the field has so far failed to identify any specific abnormalities in the expression of genes or proteins on a molecular level. 

How common is it?

Ted Bundy
A study published in 2009 surveyed a sample of 638 individuals from England, Scotland and Wales and found that 0.6% of the sample – designed to be representative of the general population – scored highly enough on a commonly used diagnostic tool to indicate "possible psychopathy"3, while a US study using the same criteria in a sample of 519 psychiatric patients found a prevalence of up to 1.2%4. While exact figures vary depending on the populations used, it is estimated that the prevalence of psychopathy in the general population lies somewhere between 0.75–1%. 

Interestingly, a literature review of 62 studies on mental disorders in prisoners concluded that up to 47% of male prisoners and 21% of female prisoners exhibited either psychopathy or antisocial personality disorder (ASPD)5, and up to 25% of the prison population could be classed as psychopaths6. This is perhaps unsurprising since psychopathy is reliably associated with persistent rule-breaking, substance misuse, unemployment and criminal behaviour. While not all psychopaths are violent criminals, many are capable of committing the most violent and heinous crimes while showing a total lack of remorse. Perhaps one of the most notorious psychopaths is the infamous serial killer Ted Bundy who, rather than showing any remorse for his violent and sickening crimes, famously said that he instead felt “sorry” for people who feel guilt. 

Although it may be difficult to empathise with such ruthless individuals, it is important to remember that since such a large portion of the most violent, repeat offenders may be categorised as exhibiting psychopathy or antisocial personality disorder, if an effective treatment for this population could be developed, it could help protect not only the family, friends and social workers of these individuals, but society as a whole. Many criminals are responsive to rehabilitation programmes, however psychopaths tend to be repeat offenders, resisting any form of treatment and displaying recidivistic criminal behaviour, and while many of the most violent psychopaths are eventually caught and put behind bars, the majority will eventually return to the community once they have served their time. Furthermore, high-security hospital care is extremely expensive; developing an effective treatment would therefore also offer a cost-benefit to health services and, in turn, to the taxpayer. 

How are psychopaths diagnosed?

Psychopathy is most commonly assessed through a structured clinical interview using a psychological assessment tool known as the Psychopathy Checklist–Revised (PCL-R), based on a combination of self-reported personality traits and recorded criminal behaviour. The Psychopathy Checklist – originally created by psychologist Robert D. Hare in the 1970’s and revised in the 1990’s – is based largely on the work of Hervey M. Cleckley, an American psychiatrist who pioneered the field of psychopathy in the early 1940’s. The PCL-R consists of 20 items scored on a three-point scale, ranking traits such as remorse, impulsivity and pathological lying. Out of a maximum score of 40, the cut-off for the label of psychopathy varies, but for research purposes it is generally accepted to be >25. Higher PCL-R scores are positively associated with traits such as manipulativeness, aggression and persistent criminal behaviour, and negatively associated with traits such as guilt and empathy. 

While it is often considered the "gold standard" for assessing psychopathy, there are numerous criticisms regarding the real-world usefulness of the PCL-R as a diagnostic tool, for instance that there may be some subjectivity in the clinician’s assessment due to their own personality traits7. Some consider it overly reductionist, noting that many of the criteria could also be signs of mania or frontal lobe dysfunction, while others have even called for the label “psychopath” to be abandoned altogether8,9. Variations have been derived for clinical use in non-criminal populations, as well as various tests separate from Hare’s psychopathy checklist, such as testing for the lack of a “startle reflex” in response to images that would normally frighten or shock people (e.g. a decapitated corpse)1

Antisocial personality disorder (ASPD) is defined as a “pervasive pattern of disregard for and violation of the rights of others”, and diagnosis commonly considers factors such as aggressive behaviour, impulsivity, deceitfulness and criminal activity. Definitions of the terms “psychopathy” and “antisocial personality disorder” often overlap in the literature, however many psychologists argue that the two are in fact distinguishable, with psychopathy being regarded as a subdivision of antisocial personality disorder. It is important to distinguish between the two, however, since Hare – the founder of the PCL-R – states that “the percentage of incarcerated criminals that meet the requirements of ASPD is somewhere between 80 and 85 percent, whereas only about 20% of these criminals would qualify for a psychopathy diagnosis using the PCL-R”. Still, neither of the two widely established systems for classifying mental disorders – the International Classification of Diseases (ICD) or the Diagnostic and Statistical Manual of Mental Disorders (DSM)  officially include a disorder titled “psychopathy”; thus, when the term “psychopathy” is used, it generally refers to individuals who have scored highly (usually >25) on Hare’s PCL-R rating scale. However, this is not a rule and definitions are often confused in the literature. To confuse matters further, the term ‘sociopathy’ is sometimes used when the subject’s behaviours are deemed to be a result of environmental influences, with ‘psychopathy’ being considered to be primarily the product of genetic, structural and functional abnormalities in the brain. For all intents and purposes, however, they can be considered one and the same and are often used interchangeably in the literature. 

The neurobiology of psychopathy and ASPD

In spite of the remarkably high prevalence, research into the neurobiology of psychopathy is surprisingly lacking. One reason for this is that it is difficult to find psychopathic subjects willing to partake in research studies, and those who do often present with other psychiatric disorders such as psychosis or drug addiction, which can be difficult to control for. Due to the populations used in such studies, the participants are also predominantly male, so there is little information on any differences between either the behaviours of or the brains of male and female psychopaths. 

Nonetheless, research over the years has highlighted a number of specific structural and functional differences in the brains of psychopaths. 

Cortical abnormalities

Since the 20th century, scientists have linked traumatic brain injury  particularly damage to the frontal cortex  with significant changes in personality, social behaviour and self-control. Most of us are familiar with the case of Phineas Gage

Normally, when the desire to satisfy primal drives is in conflict with social rules, the frontal cortex serves to control our behaviour to prevent us from getting into trouble or acting against accepted moral and social values. It warns us not to steal food from children, get into fights or have sex on the street. Certain regions of the prefrontal cortex have been associated with emotional regulation, compassion, and sensitivity to the emotions of others. 

The orbitofrontal cortex

One region which has been particularly highlighted in the context of psychopathy is the orbitofrontal cortex. Forming part of the prefrontal cortex, this region is crucial for successful reversal learning, i.e. when previously rewarded stimuli or behaviours are associated with social punishment, leading us to change our behaviour in future to avoid feelings of embarrassment or guilt. Reversal learning is known to be significantly impaired in psychopathy and ASPD. As such, antisocial behaviour may be regarded as a failure of the frontal cortex to inhibit certain parts of the brain which control the desire to satisfy primal drives and aggression10. Put simply, psychopathy is associated with a weak ability to learn to avoid behaviours that normally cause punishment through guilt or shame, and as a result, psychopaths are more likely to learn to use antisocial strategies to achieve their goals.

In support of this view, a 2013 study investigated the brains of incarcerated male adolescents using structural magnetic resonance imaging (MRI) and found that higher levels of psychopathic traits were consistently associated with decreased grey matter volumes in the orbitofrontal cortex11, among other regions. Studies dating back decades have shown significant reductions in grey matter volume in the prefrontal cortex of subjects diagnosed with ASPD – proposed to underlie the impulsive, antisocial behaviour and impaired decision-making in these individuals12

One particularly interesting MRI study13, however, compared violent offenders who met the clinical criteria for ASPD as well as psychopathy (as determined by Hare’s Psychopathy Checklist–Revised) with those who met the criteria for ASPD but not psychopathy. The results showed significantly reduced grey matter volumes in those participants who met the criteria for psychopathy in areas associated with empathy, moral reasoning and pro-social emotions such as guilt and embarrassment – attributes which psychopaths notoriously lack – compared with the participants who met the criteria for ASPD but not psychopathy. The results were significant even when factors such as IQ, substance abuse and the presence of other mental disorders were controlled for. The researchers proposed that previous studies which have reported such neurobiological abnormalities among violent offenders with ASPD may have in fact included participants with psychopathy, suggesting that it is psychopathy that is the true factor associated with these differences. 

Some studies, however, have found beneficial adaptations in the prefrontal cortex of psychopaths. A recent study14, which will be published next month in the journal Personality Neuroscience, compared structural magnetic resonance images of “successful” psychopaths – those who score high on a common self-report psychopathy scale based on Hare’s Psychopathy Checklist but are able to control their impulses and live normal lives – with ‘healthy’ controls who scored lower on the psychopathy scale. The researchers found that the “successful” psychopathic participants actually had greater levels of grey matter density in a particular brain region called the ventrolateral prefrontal cortex – a region known to be involved in self-regulation of behaviour and emotions such as fear or anger – than the ‘healthy’ controls. This difference is suggested to be an adaptive change in these individuals, and could potentially explain why some psychopathic individuals are able to be “successful” in life whereas others become repeat offenders. 

The amygdala

The amygdala
Another region thought to be important in the development of psychopathy and ASPD is the amygdala – a mass of two small, almond shaped structures located within the temporal lobes and known to be involved in the processing of emotions including fear and anger. Numerous studies have presented evidence of functional abnormalities in the amygdala in the brains of psychopaths15,16 thought to underlie the apparent lack of fear and emotion characteristic of the most extreme psychopaths. 

As well as the processing of emotions, the amygdala is also critical in the adaptation of behaviour in response to social cues. This is because the prefrontal cortex and amygdala are interconnected by an intricate network of white matter tracts. Studies have found that, in addition to a reduced overall amygdala volume15,16, the brains of psychopaths show a significantly reduced structural integrity of these white matter tracts compared to controls. A study using diffusion-tensor MRI imaging – which tracks the movement of water molecules through structures within the brain – showed that even when drug abuse, IQ and institutionalisation were controlled for, the degree of abnormality in these white matter tracts was directly correlated with the degree of psychopathy as measured using the PCL-R scale16. These white matter tracts may therefore play an important role in the failure of psychopaths to learn from and respond appropriately to social cues. 

The endogenous opioid system

People with antisocial personality disorder (ASPD) are characterised by emotional instability, impulsivity and high levels of mood and anxiety disorders, as well as high levels of substance abuse. Often, their aggressive behaviour appears to be a response to a perceived threat or a sense of frustration. 

Many of the behaviours seen in antisocial and psychopathic individuals – manipulativeness, impulsivity, failure to plan ahead – can appear almost “addiction-like” in nature. A recent theory suggests that this may be in part due to deficiencies in the natural, or ‘endogenous’ opioid system of these individuals, in that those exhibiting ASPD may feel a perpetual sense of emptiness due to a lack of natural reward, and therefore attempt to compensate for this through sensation-seeking, attention-seeking, aggressive and promiscuous behaviour and the rewarding effects of drugs10. Since individuals with ASPD also suffer from emotional dysfunction and, in the case of psychopathy, may be completely devoid of normal human emotions such as love or fear, this may in part explain why they instead resort to manipulative, violent and antisocial behaviour to fill the void. One particularly poignant scene from the BBC’s series Killing Eve depicts this concept magnificently: 

Animal studies indeed support this; mice which have been genetically engineered to express lower levels of β-Endorphin – the bodies’ natural, or “endogenous” opioid which plays an important role in pain, appetite and reward – show higher levels of aggression than healthy controls27, and mouse strains which are inherently more aggressive in behaviour express lower levels of naturally-occurring endorphins28. Furthermore, levels of impulsivity have been correlated with differences in μ-opioid receptor concentrations in healthy human subjects29, suggesting that the opioid system plays a key role in self-regulating behaviour and the ability to control our urges. 

Low glucose metabolism

Another predictor of pathological antisocial behaviour which might not seem immediately obvious is the rate at which individuals metabolise glucose in the blood. Among subjects with ASPD, abnormal glucose metabolism leading to hypoglycaemia – which has been associated with aggressive behaviour – has been identified as a strong predictor of whether or not an individual will commit violent crimes25. This may be a result of a decreased glucose uptake (leading to reduced activity) in the prefrontal cortex, resulting in an impaired ability to regulate behavioural impulses through the same neural circuitry as described above. Studies looking at the brains of violent murderers have shown significantly reduced glucose metabolism in the prefrontal cortex compared to controls26 and, further, it is proposed that such abnormalities in glucose metabolism may be the only predictor of violent crime in antisocial individuals which can surpass the efficacy of the PCL-R. 

This might suggest that substances that decrease the risk of hypoglycaemia, for example by increasing glycogen formation, might be worth considering in the treatment of individuals expressing persistent and impulsive violent behaviour.

A role of testosterone?

Finally, it is worth mentioning research linking antisocial and aggressive behaviour with hormonal differences such as increased levels of testosterone. 

Testosterone is thought to increase the propensity toward aggression by reducing activity in brain regions involved in impulse control, including the orbitofrontal cortex17. Administering testosterone to healthy subjects has been associated with a reduced fear response and impaired decision making18, and earlier studies have even suggested that testosterone may be involved in regulating empathy19 and moral decision making20. Evidence suggests that high testosterone levels increase the rates of aggressive behaviour especially when combined with low levels of serotonin21 or low levels of cortisol22

However, while early research in the field highlighted a link between testosterone and antisocial personality disorder23, more recent research has consistently indicated that testosterone levels are only loosely associated with the increased levels of aggression observed in psychopaths24. Overall, recent studies suggest that testosterone is unlikely to be of as significant importance in the development of ASPD or psychopathy as originally considered, although it may be a contributing factor when combined with other biological and social risk factors. 

Current lack of treatment

The fact that some of these abnormalities have even been detected in children with psychopathic tendencies30,31 suggests that, whether the disorder is down to genetics or a result of early childhood experiences, psychopaths seemingly fail to develop a complete set of pro-social emotions such as empathy or guilt from a very young age32

It has been proposed that, theoretically, it might be possible to develop pharmacological treatment strategies to increase the responsiveness of these systems such that, when combined with clinically based socialisation strategies (e.g. empathy training), such a treatment might allow the psychopath to learn to form more appropriate associations regarding the distress of others and actions that harm others. However, unfortunately, such a treatment has yet to surface. 

ASPD is considered one of the most difficult personality disorders to treat, and there is currently little evidence for a cure or effective treatment for psychopathy. Developing an effective treatment for either is further complicated by the inability to look at comparative studies due to the overlapping diagnostic criteria of the two disorders. 

The use of medications in the treatment of either ASPD or psychopathy is still poorly explored and no medications have been specifically approved in their treatment, although psychiatric medications such as antipsychotics, antidepressants and mood stabilizers are sometimes used to control symptoms such as aggression and impulsivity. A study in 2014 showed preliminary evidence that treatment with a low dose of clozapine – an antipsychotic commonly used in the treatment of schizophrenia – led to improvements in impulsive behaviour and reduced violence among patients in a high-security hospital with a diagnosis of ASPD with high psychopathic traits, however the study only included 7 patients and no studies have replicated these findings6

While various psychotherapies have been tried with the aim of reducing criminal behaviour in violent offenders with psychopathy, it is said that psychopaths who undergo such therapy might instead simply gain skills to become more adept in the manipulation and deception of others and thus become more likely to commit crime. 

A study published recently in Molecular Psychiatry33, however, is amongst the first to investigate specific abnormalities on a molecular level which may be amenable to pharmacological modulation, paving the way for research into potential pharmaceutical treatments in the future. 

Genetic abnormalities associated with psychopathy

For the first time, the degree of psychopathic symptoms (as measured using the PCL-R) has been directly correlated with the expression of specific genes, including genes involved in both glucose metabolism and the endogenous opioid system. 

The researchers, based at the University of Eastern Finland, used stem cells derived from participants’ skin to analyse the expression of specific genes and proteins previously associated with psychopathy or ASPD. The participants included six psychopathic violent offenders – identified by a combination of their criminal records and a clinical interview using the PCL-R – six ‘healthy’ controls, as well as three non-psychopathic individuals with substance dependence. Since psychopaths often abuse substances such as alcohol, heroin or amphetamines, including non-psychopathic substance abusers allowed the researchers to more accurately determine which genetic abnormalities were associated exclusively with psychopathy. 

Of these genetic abnormalities, the strongest association was observed for a gene called ZNF132. The exact function of this gene is unknown, but it is known to be involved in several developmental disorders. The expression of this gene, along with another gene called RPL10P9, was markedly increased among the psychopathic, violent offenders compared with the controls; furthermore, the degree of abnormality was strongly correlated with the degree of psychopathic symptoms in these participants. 

Additionally, marked abnormalities in the expression of CDH5 (cadherin 5) – a gene previously linked with aggressive behaviour34 – as well as abnormalities in the expression of the OPRD1 (opioid receptor delta 1) gene were observed in cells derived from the violent psychopathic participants compared to the controls. 

Interestingly, all of these genes with the exception of OPRD1 have previously been linked to autism33, further suggesting that they might play a role in the antisocial behaviour, emotional dysfunction and lack of empathy observed in psychopathic individuals. However, despite some similarities, there are clear differences in the deficits in empathy between psychopathy and autism15. While psychopaths tend to score highly on tests of cognitive empathy, they score low on tests of emotional empathy and high on measures of amorality. Autistics, however, show significant impairment in both cognitive and emotional empathy, but show no deficits in morality. Nonetheless, the crossover of abnormalities in the expression of genes between autism and psychopathy indeed suggests that these genes are likely to be involved in empathy and other pro-social behaviours. 

Finally, the study also found that the levels of a protein called PSMD3 was substantially lower in the cells derived from the psychopathic individuals compared with those from the controls. PSMD3 is an enzyme involved in glucose metabolism – more specifically, insulin resistance35 – and so the finding that psychopaths show significantly reduced expression of this protein owes further support to the view that abnormal glucose metabolism may be an important factor to consider in the treatment and management of severely antisocial or psychopathic individuals. 

Altogether, the abnormalities in the expression of these four genes accounted for between 30-92% of the psychopathic behaviours assessed by the PCL-R; that is to say that the differences in the expression of these genes was statistically significant enough to conclude that they are of clear importance in psychopathy. However, further research is needed to determine exactly how their expression could be modulated using pharmacological drugs (or perhaps even using newer approaches such as gene therapy), and whether this could lead to a reduction in antisocial behaviour in psychopaths. 

Potential treatments in the future?

This research is far from suggesting any specific treatment or ‘cure’ for psychopathy, however it does pave the way for future research to further investigate the role of these genes in the context of psychopathy and ASPD, with the hope of developing an effective treatment strategy for the most dangerous and recidivistic violent offenders, potentially reducing crime rates and thus improving the safety and wellbeing of the public at large. 

In light of the abnormalities observed in the endogenous opioid system of psychopaths, it is suggested that long-lasting injections of buprenorphine – an opioid medication commonly used in the treatment of addiction – could be a potential avenue to explore. Alternatively, naloxone – an opioid receptor blocker which leads to increased opioid receptor sensitivity over time – has also been considered in the treatment of ASPD10, although compliance with the treatment would be a clear difficulty in these individuals. 

However, to date, there are no controlled studies investigating the efficacy of either drug in patients with either ASPD or psychopathy. Future research should therefore focus on double-blind, controlled studies investigating the potential for these drugs to be used in the treatment of such individuals, as well as exploring the usefulness of drugs which may normalise glucose metabolism in severely antisocial individuals in order to decrease the risk of impulsive violent behaviour. Such drug treatments would ideally be combined with specifically targeted psychotherapies delivered by healthcare professionals, and would enable a more pragmatic approach to dealing with the most dangerous subsection of society. 

There is a clear unmet need for research into treatments for ASPD and psychopathy. If a treatment could be developed which could reduce the levels of impulsivity and aggression in these individuals without significant side effects, whilst allowing them to develop genuine empathy and consideration for the feelings and rights of others, it could not only reduce violent crime, but could also be of benefit to the criminal justice and health systems, as well as to the taxpayer. 

While these findings may have implications for ethical considerations regarding the criminal liability of psychopathic and severely antisocial offenders which could potentially raise questions for public policy, this falls beyond the scope of this article. 

Nonetheless, it is hoped that such research may break down some of the stigma surrounding psychopathy, so that the condition may be more effectively identified and treated with a more productive approach both within the criminal justice system and in the general population. 

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