We all know that a healthy lifestyle is beneficial for our health. But many of us forget that eating healthy, exercising regularly and getting enough sleep is also important for good mental health. In the Eat2beNICE research project a large team of researchers is investigating the link between food and mental health, specifically impulsivity, compulsivity and aggression. To share this knowledge with the rest of the world, they work together with food consultant Sebastian Lege.
The Eat2beNICE project just released a video to explain what the research is about and why it’s important. In this video Sebastian Lege visits the project coordinator Alejandro Arias-Vasquez, en several other researchers in the consortium.
From road rage and bar fights to terror attacks and global confrontations, humans tend to be an aggressive species. On the average, members of the same species cause only 0.3 percent of deaths among mammals . Astoundingly, in Homo sapiens the rate is around 2% (1 in 50), nearly 7 times higher! There are two crucial aspects that favor this kind of behavior: dwelling in social groups and being ferociously territorial. The chances are that struggle for various resources like suitable habitat, mates and food played a key role in shaping aggression in humans, favoring genetic variants that promote aggression and therefore increase changes of survival. Indeed, anthropologists who lived with exceptionally violent hunter-gatherers found that men who committed acts of homicide had more children, as they were more likely to survive and have more offspring . This lethal legacy may be the reason we are here today.
You probably know some people that could be characterized as “having a short fuse”. Perhaps you have even pondered why they seem to have such a hard time to keep their temper in check? Indeed – while scientists have known for decades that aggression is hereditary, there is another crucial component to those angry flare-ups: self-control. In humans, the impulses to react violently stem from the ancient structures located deep within the brain. The part capable of controlling those impulses is evolutionally much younger and located just behind the forehead – the frontal lobes. Unfortunately, this “top-down” conscious control of aggressive impulses is slower to act compared to the circuits of eruptive violence deep in the brain.
People who are genetically predisposed toward aggression actually usually behave more violently than the average only when provoked. People not genetically susceptible to violent outbursts seem to be better able to remain calm and “brush it off”. The ones who are predisposed in fact try hard to control their anger, but have inefficient functioning in brain regions that control emotions – in the frontal lobes . Several studies have found that men genetically susceptible to act aggressively are especially likely to engage in violence and other antisocial behavior if they were exposed to childhood abuse . Again, we see that although genes may carry certain predispositions, there are essential environmental aspects that determine the final outcome.
Early physical aggression needs to be dealt with care. Long-term studies of physical aggression clearly indicate that most children, adolescent and even adults eventually learn to use alternatives to physical aggression . Still, the importance of proper guidance and favorable environment cannot be understated. As mentioned before, Homo sapiens have been found to cause 2 percent of deaths among their fellows. However, this has fluctuated substantially throughout the history and in different cultures. During the medieval period, human-on-human violence was responsible for stunning 12 percent of recorded deaths. For the last century, people have been relatively peaceable compared to the Middle Ages, violence being the cause of death in just 1.33 percent of fatalities worldwide. In the least violent parts of the world today, the homicide rates are as low as 0.01 percent .
Our brains have evolved to monitor for danger and spark aggression in response to any perceived hazard as a defense mechanism. Aggression is part of the normal behavioral repertoire of most, if not all, species; however, when expressed in humans in the wrong context, aggression leads to social maladjustment and crime . By identifying genes and brain mechanisms that predispose people to the risk of being violent – even if the risk is small – we may eventually be able to tailor prevention programs to those who need them most.
 Gómez, J. M., Verdú, M., González-Megías, A., Méndez, M. (2016). The phylogenetic roots of human lethal violence. Nature 538(7624), 233–237.
 Denson, T. F., Dobson-Stone, C., Ronay, R., von Hippel, W., Schira, M. M. (2014). A functional polymorphism of the MAOA gene is associated with neural responses to induced anger control. J Cogn Neurosci 26(7), 1418–1427.
 Cicchetti, D., Rogosch, F. A., Thibodeau, E. L. (2014). The effects of child maltreatment on early signs of antisocial behavior: Genetic moderation by Tryptophan Hydroxylase, Serotonin Transporter, and Monoamine Oxidase-A-Genes. Dev Psychopathol 24(3), 907–928.
 Lacourse, E., Boivin, M., Brendgen, M., Petitclerc, A., Girard, A., Vitaro, F., Paquin, S., Ouellet-Morin, I., Dionne, G., Tremblay, R. E. (2014). A longitudinal twin study of physical aggression during early childhood: Evidence for a developmentally dynamic genome. Psychol Med 44(12):2617–2627.
 Asherson, P., Cormand, B. (2016). The genetics of aggression: Where are we now? Am J Med Genet B Neuropsychiatr Genet 171(5), 559–561.
Is there an ‘average ADHD brain’? Our research group (from the Radboudumc in Nijmegen) shows that the average patient with ADHD does not exist biologically. These findings were recently published in the journal. Psychological Medicine.
Most biological psychiatry research heavily relies on so-called case-control comparisons. In this approach a group of patients with for instance ADHD is compared against a group of healthy individuals on a number of biological variables. If significant group effects are observed those are related to for instance the diagnosis ADHD. This often results in statements such as individuals with ADHD show differences in certain brain structures. While our results are in line with those earlier detected group effects, we clearly show that a simple comparison of these effects disguises individual differences between patients with the same mental disorder.
Modelling individual brains
In order to show this, we developed a technique called ‘normative modelling’ which allows us to map the brain of each individual patient against typical development. In this way we can see that individual differences in brain structure across individuals with ADHD are far greater than previously anticipated. In future, we hope that this approach provides important insights and sound evidence for an individualized approach to mental healthcare for ADHD and other mental disorders.
Individual differences in ADHD
When we studied the brain scans of individual patients, the differences between those were substantial. Only a few identical abnormalities in the brain occurred in more than two percent of patients. Marquand: “The brains of individuals with ADHD deviate so much from the average that the average has little to say about what might be occurring in the brain of an individual.”
Personalized diagnosis of ADHD
The research shows that almost every patient with ADHD has her or his own biological profile. The current method of making a diagnosis of psychiatric disorders based on symptoms is therefore not sufficient, the authors say: “Variation between patients is reflected in the brain, but despite this enormous variation all these people get the same diagnosis. Thus, we cannot achieve a better understanding of the biology behind ADHD by studying the average patient. We need to understand for each individual what the causes of a disorder may be. Insights based on research at group level say little about the individual patient.”
Re-conceptualize mental disorders
The researchers want to make a fingerprint of individual brains on the basis of differences in relation to the healthy range. Wolfers: “Psychiatrists and psychologists know very well that each patient is an individual with her or his own tale, history and biology. Nevertheless, we use diagnostic models that largely ignore these differences. Here, we raise this issue by showing that the average patient has limited informative value and by including biological, symptomatic and demographic information into our models. In future we hope that this kinds of models will help us to re-conceptualize mental disorders such as ADHD.”
Wolfers, T., Beckmann, C.F., Hoogman, M., Buitelaar, J.K., Franke, B., Marquand, A.F. (2019). Individual differences v. the average patient: mapping the heterogeneity in ADHD using normative models. Psychological Medicine, https://doi.org/10.1017/S0033291719000084 .
This blog was written by Thomas Wolfers and Andre Marquand from the Radboudumc and Donders Institute for Brain, Cognition and Behaviour in Nijmegen, The Netherlands. On 15 March 2019 Thomas Wolfers will defend his doctoral thesis entitled ‘Towards precision medicine in psychiatry’ at the Radboud university in Nijmegen. You can find his thesis at http://www.thomaswolfers.com
Comorbidity, defined as the simultaneous occurrence of more than one disorder in a single patient, is commonplace in psychiatry and somatic medicine. In research, as well as in routine clinical settings.
In March 2016 the new H2020 collaborative project “CoCA” (Comorbidity in adult ADHD) was officially launched, with a 3-day kick-off meeting in Frankfurt, Germany. This ambitious project, which is coordinated by professor Andreas Reif and is co-maintaining this shared blog, will investigate multiple aspects of comorbidity in ADHD.
For instance, CoCA will “identify and validate mechanisms common to the most frequent psychiatric conditions, specifically ADHD, mood and anxiety disorders, and substance use disorders (SUD), as well as a highly prevalent somatic disorder, i.e. obesity”.
As reflected in this bold mission, most scientists trained in the biological sciences agree that studies of overlapping and concurrent phenomena may reveal some underlying common mechanisms, e.g. shared genetic or environmental risk factors.
However, particularly in psychiatry and psychology, the origins of comorbidity have been fiercely debated. Critics have argued that observed comorbidities are “artefacts” of the current diagnostic systems (Maj, Br J Psychiatry, 2005 186: 182–184).
This discussion relates to fundamental questions of how much of our scientific knowledge reflects an independent reality, or is merely a product of our own epistemological traditions. In psychiatry, the DSM and ICD classification systems have been accused of actively producing psychiatric phenomena, including artificial diagnoses and high comorbidity rates, rather than being “true” representations of underlying phenomena. Thus, the “constructivist” tradition argues that diagnostic systems are projected onto the phenomena of psychiatry, while “realists” acknowledge the presence of an independent reality of psychiatric disorders.
In an attempt to explain these concepts and their implications, psychiatric diagnoses and terminology have been termed “systems of convenience”, rather than phenomena that can be shown to be true or false per se (van Loo and Romeijn, Theor Med Bioeth. 2015, 41-60). It remains to be seen whether such philosophical clarifications will advance the ongoing debate related to the nature of medical diagnoses and their co-occurrence.
CoCA will not resolve these controversies. Neither can we expect that our new data will convince proponents of such opposing perspectives.
It is important to acknowledge the imperfections and limitations of concepts and instruments used in (psychiatric) research.
However, it may provide some comfort that similar fundamental discussions have a long tradition in other scientific disciplines, such as physics and mathematics. Rather than being portrayed as a weakness or peculiarity of psychiatric research, I consider that an active debate, with questioning and criticism is considered an essential part of a healthy scientific culture.
Hereby, you are invited to join this debate on this blog page!
In his most famous book, Walden, the American author and naturalist Henry David Thoreau wrote that “many men go fishing all of their lives, without knowing it is not fish they are after”. Thus, one of the difficulties encountered when studying behaviour is to understand their underlying motivation. What makes some animals aggressive and other not when faced with the same situation? How does the brain process stimuli to generate an appropriate behavioural response?
A recent study by Golden and colleagues (Golden et al., 2016) has investigated this question in mice. They combined the resident-intruder assay (a rodent aggression test) with a condition place preference (CPP) test for reward behaviour. The resident-intruder test measures the response of a mouse towards an intruder in its home cage. In this case, male CD-1 mice were allowed to interact with a subordinate C57BL/BJ intruder. Aggressive contact was recorded as the latency for CB-1 mice to attack. Interestingly, about 70% of CD-1 mice were aggressive in this setup (AGGs) and 30% were non-aggressive (NONs). The CPP pairs a neutral stimulus (in this case one side of the home cage) with a conditioned stimulus – the intruder mouse. If the conditioned stimulus is rewarding then test animals spend more time on side of the cage where it was encountered. Here, CD-1 were permitted to interact with C57BL/6J intruders on one side of the CPP setup, whereas the non-conditioned side was empty. AGGs show a positive change in preference under these conditions where NONs showed aversion – they kept away from the intruder. This suggests that AGGs find the aggressive stimulation rewarding and actively seek out the interaction with C57BL/6J.
The authors next examined the neural circuits that control this behaviour with a focus on the connection between the basal forebrain and lateral habenula. During formation of aggression mediated-CPP AGGs show increased forebrain activation (in the nucleus accumbens, diagonal band and lateral septum) with a simultaneous reduction in habenula activity. Next, state of the art optogenetic techniques were used to either activate or inhibit the habenula. Stimulation of the forebrain-habenula circuit in NONs caused a positive change in place preference, whereas inhibition of this circuit in AGGs decreased CPP: the valency of the C57BL/6J stimulus mouse had changed! Importantly, optogenetic stimulation did not alter other social behaviours, although both the intensity of aggression and the rewarding properties of cocaine were increased.
This is exciting research that has possible translational potential to other species. The habenula (and in particular its interaction with the forebrain) appears to be important in processing of stimuli that can elicit aggression. In humans, deep brain stimulation of the basal forebrain and habenula has already been achieved suggesting a possible future treatment for pathological aggression.