Research

Is it possible to predict binge drinking?

IMAGEN researchers investigated different factors associated with alcohol use in adolescents and explored whether it was possible to predict binge drinking, defined by the NHS as “drinking heavily in a short space of time to get drunk or feel the effects of alcohol”. Examining data from IMAGEN participants, researchers found that approximately 40 different variables acquired at age 14, such as personality traits, our genes, our history (i.e., smoking, accidents), and how our brain responds to rewarding events, could predict whether an individual would go on to binge drink at age 16 with approximately 70 percent accuracy. Life events, such as a romantic or sexual relationships, and personality measures (i.e., novelty seeking) were amongst the strongest classifiers for both current and future binge drinkers. Importantly, the researchers concluded that the prediction of future binge drinkers relied heavily on aspects of personal history, personality, as well as brain structure and activity.

This model gives us an understanding of the relative roles of brain structure and function, personality, environmental influences and genetics in the development of adolescent abuse of alcohol. This research is important because understanding what the risk factors are for the development of alcohol use behaviour means we identify who is most at risk in the future. This work can help to inform the development of specific early interventions in carriers of the risk profile to reduce the incidence of adolescent substance abuse.

Breakdown of variables found to predict future binge drinkers

Reference: Whelan, R., et al., (2014) Neuropsychosocial profiles of current and future adolescent alcohol misusers. Nature. DOI: 10.1038/nature13402

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Effect of Genes on Brain Region Size

Data from the IMAGEN study has been used to identify common genetic differences that influence the development of regions in the subcortical (interior) part of the brain, under normal developmental conditions. This research was through a collaboration of nearly 300 scientists from 193 institutes across the world, pooling genetic data and MRI scans from over 30,000 individuals. This is part of the global ENIGMA project, one of the leading groups helping to better understand brain structure and development. IMAGEN is a major contributing member to this project.

Brain and genetic data from over 30,000 individuals ranging in age from 9-97 years old were included in the analyses. The researchers identified several common genetic variations that were related to the size and shape of subcortical brain structures.

The identification of genes that influence the size of individual brain regions in a healthy population helps us to understand the genetic mechanisms that are important for brain development. Such information may eventually unravel the biological basis of mental disorders. Specifically, it will help us link psychiatric symptoms to the relevant brain region and will improve understanding of neurological and neuropsychiatric diseases such as Parkinson’s disease, Alzheimer’s disease, epilepsy and schizophrenia that are associated with size differences in some of the subcortical brain regions investigated.

Shape analysis in 1,541 young healthy adolescents shows how the common genetic variation, called rs945270, is related to increases in volume in a subcortical structure, the putamen. Red indicates greater volume.

Reference: Hibar DP, et al., (2015). Common genetic variants influence human subcortical brain structures. Nature. 2015 Apr 9;520(7546):224-9. doi: 10.1038/nature14101. Epub 2015 Jan 21.

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Adolescent drinking could be driven by altered DNA

Research from the IMAGEN study has found that alterations in our DNA may affect adolescent drinking. Researchers noted that changes in a particular gene, likely impacted by environmental factors, were associated with an increase in drinking over a two-year period. This epigenetic change was also linked to increased impulsive behaviour. Both increased drinking and impulsivity elevate the risk of developing a future alcohol use disorder. These findings suggest that changes in gene expression may influence impulsivity by altering activity in an area of the brain responsible for behavioural control.

Association of expression of gene PPM1G and activation of the subthalamic nucleus during an impulsivity-based task (Stop Signal Task) in 393 adolescents. Yellow indicates greater activity.

Reference: Rugerri, B. et al (2015) ‘Association of Protein Phosphatase PPM1G With Alcohol Use Disorder and Brain Activity During Behavioral Control in a Genome-Wide Methylation Analysis’. American Journal of Psychiatry

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Examining the link between cognitive ability and brain structure

Cortical thickness, the thickness of grey matter in our brain, has been linked with a number of cognitive abilities. Knowing this, IMAGEN researchers investigated different genes that might be involved in brain development and cortical thickness in adolescents.

The study found that a variation within the NPTN gene was associated with cortical thickness in the left brain hemisphere, particularly in the frontal and temporal lobes. The researchers also noted an association between cognitive ability and cortical thickness. The genetic variation affects the expression of the NPTN gene, which encodes a protein that might affect how brain cells communicate with each other. These findings help our understanding of the variability in cognitive ability among healthy people and what impacts this variability.

Visual demonstration of cortical thickness. This picture is obtained from a structural brain scan (MRI). The point of view is as if you are looking at the brain head-on.

Reference: Desrivières, S. et al., (2015) ‘Single nucleotide polymorphism in the neuroplastin locus associates with cortical thickness and intellectual ability in adolescents’ published in Molecular Psychiatry

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Is there a ‘binge drinking gene’?

IMAGEN researchers investigated how the RASGRF-2 gene, which is linked to increased alcohol consumption in a prior human study, might relate to different patterns of brain function in adolescents. This could give us clues as to why some teenagers drink more than others.

The researchers found that boys with a specific variation of the RASGRF-2 gene showed stronger activation of the ventral striatum area of the brain when they were waiting for a reward. This suggests that there is a link between the RASGRF-2 gene and how sensitive we are to rewards, both in terms of behaviour and brain activity. The researchers conducted a follow-up study at age 16 and found that adolescents with this variation of the RASGRF-2 gene drank alcohol more frequently. This finding is important as it might help us identify risk factors for early alcohol use and may help us develop addiction prevention and treatment strategies in the future.

The top two panels show activity across the whole brain during reward anticipation and reward feedback. The bottom panel shows that there is an association between RASGRF-2 variation and brain activity in the ventral striatum. Yellow indicates stronger activity.

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Reference: Stacey, D., et al. (2012). RASGRF2 regulates alcohol-induced reinforcement by influencing mesolimbic dopamine neuron activity and dopamine release. Proceedings of the National Academy of Sciences,109(51), 21128-21133.

Genes associated with networks of activity between different brain regions.

Thanks to prior research, we already know that essential brain functions like vision, memory, and attention are performed by networks consisting of several discrete brain regions rather than by individual brain regions working alone. These regions are anatomically connected and share ‘functional connectivity,’ meaning that activity in these regions is tightly linked. These connections in brain activity can still be seen, even when we are resting.

IMAGEN researchers have established that our genes play a role in synchronized signals being sent between different brain regions. They found that 136 genes are related to the strength of these brain activity networks in individuals when they are resting in an MRI scanner. Some of the identified genes are implicated in neuropsychiatric conditions like Alzheimer’s and schizophrenia that are partially characterised by dysfunctional network connectivity. Therefore, this research lays important groundwork for understanding how gene-brain relationships are vital for normal functioning as well as disease.

Functional networks in brain activity and gene expression data. Panel A shows four large connectivity networks during rest. Panel B shows how expression of the genes groups together in similar functional networks.

Reference: Richiardi et al., (2015) BRAIN NETWORKS. Correlated gene expression supports synchronous activity in brain networks. Science. 2015 Jun 12;348(6240):1241-4. doi: 10.1126/science.1255905. Epub 2015 Jun 11.

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Researchers identify genes that may play a role in regulating how much alcohol we drink

Alcohol consumption is known to be moderately inheritable; however, the genetic basis in humans is still largely unknown. IMAGEN researchers have identified a gene that may be responsible for regulating how much we drink. Using genome-wide association (GWAS) methods, researchers analysed DNA samples from over 26,000 people, including IMAGEN participants. They identified a natural variant in the ‘autism susceptibility candidate 2’ (AUTS2) gene as being related to alcohol consumption. AUTS2 has previously been linked to autism and ADHD, but its function is still unknown.

Once the researchers had identified AUTS2, they characterised its expression in the brain using samples of donated human brain tissue. The researchers found that the gene was most active in the areas of the brain associated with reward mechanisms, which suggests it might play a part in regulating the positive reinforcement that people feel when they drink alcohol. These results help us better understand the biological basis for alcohol drinking behaviour. This is an important first step towards the development of individually targeted prevention and treatments for alcohol abuse and addiction.

Reference: G Schumann, LJ Coin, A Lourdusamy, P Charoen et al., 2011. Genome-wide association and genetic functional studies identify autism susceptibility candidate 2 gene (AUTS2) in the regulation of alcohol consumption. Proceedings of the National Academy of Sciences, 2011

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Brain regions related to substance use and ADHD related behaviour identified in adolescents

Although attention deficit hyperactivity disorder (ADHD) and substance abuse have both been linked to more impulsive behaviour, the brain networks underlying such impulsivity have not yet been identified.

IMAGEN researchers used fMRI to examine brain activity in nearly 2,000 adolescents as they attempted to stop a movement in response to an unpredictable ‘stop’ signal. In general, more impulsive people find this task harder, and drug users, as well as individuals with ADHD, take longer to respond to the ‘stop’ signal. The researchers found that the adolescents with ADHD symptoms and those who had used drugs or alcohol did the task equally well, but only the teenagers who used drugs or alcohol in early adolescence were more likely to have reduced activity centred around a brain area known as the orbitofrontal cortex (an area important for impulse control and related to drug–seeking behaviour). In contrast, activity in another brain area, the right inferior frontal cortex, was modulated specifically by the use of illegal drugs, rather than tobacco and alcohol. The change in brain activity here correlated with how often illegal drugs were used, suggesting that this change may be caused by the repeated use of such drugs, rather than a pre-existing difference.

These results demonstrate how a particular behaviour (i.e., impulse control) common to ADHD and substance use may result from activity in different brain networks.

A graphical representation of the differences in network activation and Stop Signal Reaction Time (SSRT). Individuals with faster ‘stop’ reaction times had higher brain activity.

Reference: R. Whelan et al. 2012. Adolescent impulsivity phenotypes characterized by distinct brain networks. Nature Neuroscience 15: 920-925. doi:10.1038/nn.3092.

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Specific brain regions found to activate in adolescent smokers when they expect a reward

It is thought that adolescents have a particular vulnerability to addictive behaviours. Furthermore, the majority of adult smokers began smoking during adolescence. IMAGEN researchers were interested in uncovering what connections within the brain were responsible for this increased vulnerability to nicotine dependence. They examined MRI brain scans in 43 IMAGEN participants who smoked and 43 IMAGEN participants who had never smoked. While undergoing the brain scan both groups of participants completed a task where they had to press a button to win money.

Compared to non-smokers, the group of adolescents who smoked showed significantly lower neural activity in the ventral striatum, the part of the brain responsible for processing rewards, when expecting a reward from the gaming task. Researchers found that the amount of activity within this area of the brain was also associated with frequency of smoking, with more frequent smokers having less brain activity in this region. These results were the same even for smokers who had fewer than ten incidents of smoking in their lifetime, which suggests that individuals with lower activity in the ventral striatum may be more vulnerable for developing an early nicotine addiction.

Response to reward anticipation in the ventral striatum of adolescent smokers versus non-smokers. Panel B shows smokers had less reward-related activity in the putamen and ventral striatum compared to non-smokers (Panel A). Panel C shows that greater smoking frequencies were associated with smaller brain activation.

Reference: Peters J, Bromberg U, Schneider S, Brassen S, Menz M, Banaschewski T et al (2011). Lower ventral striatal activation during reward anticipation in adolescent smokers. Am J Psychiatry 168: 540–549.

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Risk taking and the adolescent reward system: a potential common link to substance abuse.

Risk-taking increases during adolescence, including experimentation with alcohol and drugs. Previous research has linked problematic substance use with abnormalities in reward processing in the brain. IMAGEN researchers were interested in investigating whether links existed between increased risk-taking in adolescence and reward processing abnormalities associated with substance use.

Researchers looked at brain scans from 266 healthy IMAGEN participants and 31 participants who had reported problems with substance use. They also gauged the teenager’s propensity to take risks by looking at their performance on a gambling task. The researchers found that the riskier the behaviour participants displayed the less brain activity was seen in the ventral striatum, the part of the brain crucial for processing rewards, when participants were expecting a reward. Greater risk-taking behaviour was also found to be associated with lower grey matter density in the ventral striatum. Those with substance use problems, on average, showed more risky behaviour and had less activity in the reward centres of the brain than their healthy counterparts.

However, because this link between riskier behaviour and less activity in the ventral striatum of the brain was observed even in participants without any substance use, it suggests that a link between risk and the reward processing exists even before the onset of substance use. This means that some participants may be predisposed to drug addiction and this research may help us to identify who is most at risk of development substance issues in the future.

The relationship between risk-taking behaviour with striatum activity and structure. Panel A shows increased risk-taking behaviour is associated with lower brain activation during the anticipation of receiving a reward. Panel B shows increased risk-taking behaviour is associated with lower grey matter density.

Reference: Schneider S, Peters J, Bromberg U, Brassen S, Miedl SF, Banaschewski T, Buchel C. Risk taking and the adolescent reward system: a potential common link to substance abuse. American Journal of Psychiatry. 2012;169(1):39–46.

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What predicts early alcohol use in healthy adolescents?

Recent research suggests that individual differences in sensitivity to receiving a reward have an important role in early substance use. Now IMAGEN researchers have examined whether other individual differences in personality, behaviour and brain activity may also increase the risk of developing substance abuse.

Researcher’s analysed data from 324 healthy IMAGEN participants at age 14 in order to develop a model to predict alcohol use. They found that reward-associated behaviour, personality (extraversion, novelty seeking, sensation seeking, and impulsivity), and brain activity all contributed to higher levels of alcohol consumption. Interestingly, personality contributed more to adolescent alcohol use than behaviour and brain activity. The combination of reward-related personality traits, behaviour, and brain activity predicted 26% of early onset drinking in teenagers. Because these factors may increase the risk for later alcohol abuse in adolescence, they provide important insight into what underlies the development of substance use disorders.

Brain activation when participants are anticipating a large reward when playing a game in the MRI. Yellow indicates stronger brain activity.

Reference: Nees, F., Tzschoppe, J., Patrick, C.J., et al. (2011). Determinants of early alcohol use in healthy adolescents: the differential contribution of neuroimaging and psychological factors. Neuropsychopharmacology, 37,986–995.

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