What is drug addiction?

Amy Winehouse was a terrific talent and one of my favourite recording artists of all time. Her songs seamlessly blend R&B, soul, hip hop and jazz and her second album ‘Back to Black’ won 5 Grammys, making her the only British female artist to achieve such success in a single night at the famous award ceremony. She also struggled with substance abuse. To what extent remains largely unknown but her death has fuelled debate as to the precise nature of drug addiction and how it should be addressed by society as a whole. I thought it poignant therefore to delve into the neuroscience of addiction and see if I can’t shed some light as to why people behave in the often self-destructive manner in which they do and how, if at all, they might be helped. Now, you might think that this is a spectacularly hard task. Surely, drugs of abuse (such as amphetamines, cocaine, opiates, alcohol and nicotine) have a broad range of actions that are wholly dissimilar from each other? Well, that is partly true, but when it comes to their addictive properties, they have more in common than you might think. What constitutes drug addiction? Drug addiction, as most will know, develops as a result of chronic exposure to a particular substance. People who are addicted to a drug show similar patterns of behaviour. These include: 1. A compulsion to seek the drug 2. An inability to control the amount of drug consumption 3. A negative emotional state when subjected to periods of withdrawal (defined as Substance Dependence by the Diagnostic and Statistical Manual of Mental Disorders [DSM] of the American Psychiatric Association) Neuroscientists have sought to understand the neural mechanisms underlying these behaviours for generations and emerging from these studies is the concept of the ‘reward circuit’ that seems to be involved in the development and maintenance of drug addiction. Now, a lot of neuroscience (indeed any science) is about gradually building up a picture from fragments of information. In most cases, that information may not even come from human subjects but from animal models. That means that current ideas regarding drug addiction are far from unequivocal, but from looking at the correlations between how the rodent brain and human brain are altered during the development of drug addiction, we can make careful assumptions about what might be the general rule. You see, the brain behaves a little bit like a factory, with different departments responsible for producing a certain sort of feeling or behaviour. This means that there are anatomically distinct areas that are concerned with happiness, memory, movement and so on. This is (as ever) an oversimplification, as it is usually the concerted action of several brain regions that lead to emergence of a particular thought or action. However, it is useful to think of the brain in this way, particularly when analysing how brain circuits are altered in drug users. The reward circuit The reward circuit consists of several brain regions that are heavily interconnected; each with distinct - but related - functionality. These include the nucleus accumbens (a brain region that is extremely well documented for its involvement in drug addiction), the ventral tegmental area, the amygdala, the prefrontal cortex, the hippocampus and the insula, among others. Dysfunction in each of these areas has been implicated in the onset and maintenance of drug-addiction, each area being responsible for a slightly different facet of the drug-addicted mental state. The nucleus accumbens: pleasure Now, the nucleus accumbens is known as the reward centre of the brain. Largely because in various different experimental paradigms, subjects that report that they are experiencing reward show increased activity in this area. This can be whilst taking drugs of abuse or simply eating, engaging in sexual activity or indeed anything associated with pleasurable reward. All drugs of abuse raise the level of a chemical known as dopamine in the nucleus accumbens and it is this elevation in dopamine (initiated in different ways by different drugs) that is responsible for the feeling of euphoria associated with drug intake. However, persistent activation of the nucleus accumbens leads to the development of drug addiction, primarily due to persistent changes in the level of dopamine, which leads to an alteration in how people respond to otherwise rewarding stimuli. Put simply, after disruption of the dopamine levels in the nucleus accumbens, people get less satisfied with things that aren’t their drugs of choice. Furthermore, people derive progressively more pleasure from the drug in question, exacerbating the effect. The amygdala: fear On the flip side of the coin, the amygdala is a region of the brain situated right next to the nucleus accumbens but is often associated with feelings of fear and anxiety. As opposed to the positive reinforcement created by the nucleus accumbens, it is during withdrawal that the amygdala seems to have its largest role. Basically, as access to the drug is taken away, stress-related hormones are increased in the amygdala which can lead (at least partially) to the negative feeling associated with withdrawal. The hippocampus: memory The hippocampus is an area of the brain that is associated with learning and memory as well as the ability to perform tasks requiring spatial navigation, such as finding your way around a building. It is also important for ‘contextual-conditioning’, meaning that it enables the mind to establish links between an environmental cue (a nightclub, for example) and a memory (such as taking a drug.) Activation of the hippocampus is implicated in initiating cue-induced drug-seeking behaviour. Indeed, it has been shown that cue-induced craving of drugs (eg. the feeling of needing a drink in a pub or a cigarette with a cup of coffee) is associated with an increase in activity in the hippocampus (as well as the amygdala) in humans, indicating that normal memory function may be being encroached upon by drugs of abuse. The prefrontal cortex: decision The prefrontal cortex consists of several subdivisions including the orbitofrontal cortex and dorsolateral prefrontal cortex. These areas have a variety of different functions but are often described as being imperative in carrying out decision-making processes in response to internal/external-cues, a process known as executive function. It is believed that the activity of the prefrontal cortex is disrupted in subjects who are addicted to drugs. This may go some way to explaining why drug users often make poor decisions regarding drug intake (ie. pursuing a drug whilst fully aware of the negative impact drug intake will have on them and the people around them.) So... As complicated as that may have sounded, it represents a gross oversimplification of what actually goes on in the mind of a drug addict. I simply wanted to introduce you to some of the concepts that are emerging as a result of neuroscientific research and give you a flavour of what is to come in future posts. As I move through my journey into drug addiction, I will make constant references to the reward circuit and its components and so an introduction was necessary to familiarise you with the brain’s machinery. In my next article, I will be describing how alcohol usurps the reward circuit to create the mind of an alcoholic, so stay tuned... Suggested reading Neurocircuitry of addiction. Koob and Volkow. (2010) Addiction and brain reward and antireward pathways. Gardner. (2011)

SfN 2011 - Day one

Yesterday saw the opening of Neuroscience 2011, the hottest event in the neuroscience calendar. As promised, our team (me) was on the scene to bring you all of the highlights live, direct and in technicolor. Well, not exactly ‘live’, as I have only just got round to writing about them. Jet-lag and wine hit me like Pauline Fowler’s frying pan last night and so I felt I was unable to do the article any justice. Instead, I have woken up at 5:30 am in the morning in order to relay all of the best bits of yesterday before trundling in to the Walter E. Washington Convention Center to be bamboozled by yet more revelations in brain science.

Day 1 highlights:

Robert J. Shiller

Bob Shiller is an eminent economist, graduate from MIT and author of the recent book ‘Animal Spirits: How Human Psychology Drives the Economy, and Why It Matters for Global Capitalism’. Given the title of his book, one might have assumed that his presentation, the inaugural address of the meeting, would be about how human behavioural psychology - or perhaps even neuroscience - affects the financial markets. Those (such as myself) who assumed this were left disappointed, as the link between psychology and the economy was never really established. This should not have been surprising given the paucity of knowledge regarding the human brain and the woeful lack of understanding for the capricious nature of the global financial system; but it was disappointing nonetheless.

However, the talk was still fascinating and stimulating, and provided neuroscientists with a glimpse of the challenges that face economists on a daily basis. Shiller consistently drew comparisons between the brain and the economy throughout, illustrating clearly that both systems consist of interconnected units that are subject to spontaneous activity that can not always be predicted. The difference, he argued, is that whilst neuroscientists have the luxury of being able to perform controlled scientific experiments to test hypotheses, economists must produce treatises based on observations alone. This problem is further complicated by the fact that the financial markets are continuously in flux and so the thing that they are trying to study doesn’t even have the decency to remain constant, not even for a minute.

I left Shiller’s talk feeling that I understood the financial markets even less than when I walked in, but was reassured (although concerned) by the revelation that economists understood it far less than I had previously assumed. The analogy between brains and markets may prove to be a fruitful one, and could possibly assist with the development of novel techniques to facilitate economic research. Ultimately though, the underlying take-home message of this talk was that nobody can predict the vicissitudes of the economy because, ultimately, they are governed by the actions of imperfect, irrational, animal spirits.

Craig Stark

The first talk of the symposium ‘Neuroscience and the Law’ was presented by Craig Stark. In it, he demonstrated his research on ‘false’ memories and how they can be as real to the person who perceives them as normal memories and how dangerous this can be. For instance, his first example consisted of a case in Australia of a man who was arrested on suspicion of rape. The victim had provided police with a description that fit the appearance of the arrested man perfectly. Furthermore, when presented with photos of the man in question, the victim affirmed that he was indeed the attacker. The man denied this, and claimed that at the time the attack took place he had an alibi: he was on live TV. In fact, this transpired to be the case; the man was on a live discussion panel with the chief of police and the local bishop. Alibis don’t get much better than that! However, even in the face of this damning evidence to the contrary, the victim still maintained that he was indeed the attacker, proclaiming in court, clearly in some distress, ‘don’t you think I would know who attacked me?’

Throughout his talk, Stark outlined some of the work he and others have been doing to establish how we obtain false memories. It is important to note that this does not simply refer to misremembering information flippantly or being unsure of certain facts. These false memories seem very real to those that have them (presumably all of us to some degree) and their validity will be vehemently defended until they can be proved false. For instance many of us have memories of where we were when certain things happened (Kennedy getting shot, September the 11th, etc.), but Stark argues that, over time, false memories based on our expectations can easily replace reality, such that much of the time these believes are in fact false, but we have no way of knowing.

The results produced in Stark’s laboratory have important implications for the judicial system. Should we trust eye-witness accounts at all? If so, when should they be trusted and how can we know? An important thing to note is that, in this instance, lie-detector tests are completely useless, as subjects with false memories believe that they are telling the truth and so any indicator of their honesty will not help. However, Stark believes that different (however marginally different) neurological pathways are activated when retrieving false and genuine memories, and so there is potential for the development of brain scans that measure truth in the future. This would be a fundamental leap in the justice system and, as he conceded, would be pretty scary!

Other bits...

The aforementioned talks were definitely my favourites of the day, but there were several other good talks. For instance, Abigail Baird gave a wonderfully lively (and humorous) talk outlining the difference between the way the adolescent and adult brains process information and work out how to behave. Teenagers are slower than adults at assessing what to do in a given situation (such as whether or not to swim with sharks; ostensibly quite a simple question) and use fundamentally different areas of the brain, presumably because they have to ‘think about it’ naively, rather than base decision-making on prior experience. Furthermore, adolescents are heavily influenced by peers during moments of decision-making (no surprise there), and use completely different brain regions to solve problems when in the presence or absence of people their own age.

As usual, the first day of Neuroscience was as tiring as it was stimulating and today promises to be no different. Possible highlights include Andreas Luthi’s talk on the neurobiology of fear, a symposium on the neurological basis of the placebo effect and a talk by Theodore Mcdonald entitled ‘The Self and Neuroscience From an Indian Philosopher's Perspective’. Who knows though, you can’t predict what’s going to happen at a neuroscience conference. I guess they are like financial markets in that respect...

Dr Paul

'Terry Pratchett: Choosing to Die' series part 1: Alzheimer's disease

Terry Pratchett is probably the most well-known person to have a particular form of dementia known as Alzheimer's disease and in his recent documentary he revealed that having the disease is making him contemplate assisted suicide. But what is Alzheimer's disease and why haven't neuroscientists cured it yet?


Alzheimer's disease is a neurodegenerative disease, which means that neurones (brain cells) in the brains of sufferers begin to degenerate and, as a consequence, regions of the brain (such as the hippocampus and parts of the cerebral cortex) shrink severely as the disease progresses.

Common symptoms include loss of memories, loss of the ability to form new memories and loss of the ability to perform complex motor functions. All of these symptoms worsen with time and eventually lead to an inability to perform even the simplest function and then death.


What are neuroscientists doing to help?


Alzheimer's disease is probably the most studied illness of the brain and represents one of the major challenges for neuroscientists of our time. But given the intensity of the research in this area, surprisingly little is actually known regarding what causes the disease.


However, there are two main theories (which are not mutually exclusive) about what may be the cause. These involve a protein, a peptide and lot of tangling.


First, a word on proteins. For people not involved in the biological sciences, the word 'protein' may conjure up images of bodybuilders or the information found on the back of food packets. But proteins are responsible for a lot more than building body mass. They are the building blocks of life, and the complex interplay of the different proteins that exist in your body govern how you think, feel and respond.


Proteins serve many purposes in the human body and can take many forms. However, they are all made out of the same little units (amino acids), which can be arranged in a multitude of different ways.


One of these proteins, known as tau, helps to stabilise microtubules (part of the cell skeleton that determines the shape of the cell and assists the transport of molecules within it.) In Alzheimer's disease, this protein attaches itself to other tau proteins inside the cell to cause a tangled mess of proteins, known as neurofibrillary tangles. This may be one of the causes of the neurodegeneration that occurs during Alzheimer's.


Now, a peptide is just a smaller version of a protein, and a peptide known as amyloid beta may also be one of the contributors to the onset of Alzheimer's disease for a very similar reason. Different forms of amyloid beta can attach to each other to form complexes known as 'plaques' and these plaques are observed in the brains of patients who have died from Alzheimer's disease. Furthermore, some forms of amyloid beta may actually be toxic by themselves.


So, at present, neuroscientists believe that these protein tangles and peptide plaques may hold the answer to why neurones begin to degenerate following the onset of Alzheimer's disease, but has this helped with its diagnosis or treatment?


How do you know someone has Alzheimer's disease?


The short answer to this question is: you don't. Well, not for certain at least.


At present, psychological assessments can be made that can distinguish patients with Alzheimer's disease from patients without dementia with a high degree of accuracy, but these fail to accurately detect differences between patients with other forms of dementia and Alzheimer's.

Brain scans such as CT (computerised tomography) and MRI (magnetic resonance imaging) can be used in conjunction with psychological assessments to rule out other pathologies that might be causing the observed symptoms, such as tumours.


But the real problem is that the symptoms of Alzheimer's disease are so similar to a range of other illnesses that lead to dementia, diagnosis is extremely difficult.


However, because of the work achieved within neuroscience research, techniques that measure the amount of amyloid beta and tau protein present in the circulation of patients are now being employed in order to assess possible Alzheimer's sufferers.


In reality, a range of different techniques involving those mentioned as well as other complimentary procedures will need to be utilised to unequivocally diagnose a patient with Alzheimer's disease. But once a patient has been diagnosed, what can be done to treat them?


What can be done to treat Alzheimer's disease sufferers?


Unfortunately, at this point in time, relatively little.


There are some treatments available that do improve cognitive function once it has declined, such as memantine and cholinesterase inhibitors. Also, improved social interaction and aromatherapy offer non-pharmacological alternatives to the aforementioned treatments. However, these treatments appear to have only limited effects and do not cure the disease.


For obvious reasons, attempts to find a cure for Alzheimer's disease have centred around the prevention of amyloid beta plaque and neurofibrillary tangle formation.


Unfortunately, immunotherapy techniques (which utilise antibodies) that have cleared amyloid beta fragments from Alzheimer's patients have been ineffectual in curing the disease. In fact, no treatment that has targeted amyloid beta has been effective. This has sparked debate as to the role of amyloid plaques in causing the disease.


It isn't all bad news though. Some promising results have begun to emerge from treatments designed to disrupt the formation of neurofibrillary tangles and these may turn out to be the treatments of the future, once they pass through the necessary medical trials.


Can I stop myself getting Alzheimer's disease?


Well, no one knows exactly how to prevent Alzheimer's, but there are several risk factors that are associated with the development of the disease.


There are a couple of things that you are powerless to stop that increase your chances of getting Alzheimer's disease, such as age, genetic make-up and if you sustain a head injury. There are also treatable conditions that are associated with an increased risk of developing the disease, such as stroke and diabetes.

But there are also several things you can change as a matter of lifestyle that can lower your chances of developing Alzheimer's. These include (yes, you guessed it) decreasing alcohol consumption, having a healthy, balanced diet, increasing the amount you exercise and giving up smoking. Also, there are some reports that an increase in social activity and having a mediterranean diet may reduce your chances too.


Alzheimer's disease is a complex condition. It is hard to diagnose, to treat and to work out what is causing it. Progress will take time, but there is hope on the horizon. Neuroscientists are working tirelessly to find a cure (and secure a nobel prize) and they have already made important steps in determining the cause of the pathology.


While they are working on it, the best advice I can give for preventing Alzheimer's is: Stop drinking and smoking and eat more fresh fish and pasta!


In all seriousness, Alzheimer's disease causes turmoil for those who suffer from it and those who care for them. Patients are often aggressive and can become depressed. This, coupled with the fact that they often lose all recollection of the identity of their loved ones, makes caring for a patient with Alzheimer's an extremely stressful experience. I sincerely hope that a cure can be found soon.

Terry Pratchett and assisted suicide

I have just finished watching the programme 'Terry Pratchett: Choosing to Die', a documentary on assisted suicide, or euthanasia, which was aired last night on BBC2. Wow. Pretty intense stuff. I watched the whole programme knowing that I was going to watch a man die at the end. 

Sure enough, viewers were able to watch an extremely brave man named Peter Smedley put an end to his life in a little blue house in Geneva by ingesting a poison (which I believe to be pentobarbitol, but may be mistaken) and gently falling asleep.

There were 3 men in this programme that had chosen to take their own lives. One was Peter, another was named Andrew and the final one was the presenter himself, Terry Pratchett. By the end of the programme, only Terry was still alive, left to ponder his future after seeing firsthand what the procedure of assisted suicide entails.

I was going to write a blog on the programme itself, but having watched it, I think that it would be more helpful if I told you a little bit about the illnesses that were making these men contemplate assisted suicide.

All of them were neurological disorders (Alzheimer's disease, multiple sclerosis and motor neurone disease), which just goes to show how important neuroscience research will be in enhancing the lives of future generations.

In my next 3 blog posts I would like to give a brief overview of Alzheimer's disease, multiple sclerosis and motor neurone disease; their prevalence, symptoms and treatments but more importantly, how close neuroscience is coming to a cure.

Stay tuned for the first instalment... 

Structural differences in brain correspond to political inclinations... so Colin Firth reckons

If people hadn't heard of Colin Firth last year, they will have heard of him now. The British actor has had a sensational year following his performance in 'The King's Speech', which bagged him the best actor award at the oscars.

But Mr Firth has also been dabbling in neuroscience this year. In April, he was coauthor of a neuroscience paper entitled 'Political orientations are correlated with brain structure in young adults' that was published in Current Biology.

In reality, Mr Firth did little of the actual research for the article, but was one the driving forces behind the project after he commissioned the study whilst appearing on BBC Radio 4.

In the article, the authors used functional magnetic resonance imaging (fMRI; a type of brain scan) to analyse the brain size of people with different political inclinations. They found that people who vote for liberal parties and people who vote for conservative parties show differences in the size of some of their brain regions.

More specifically, liberal people had a greater volume of gray matter in the anterior cingulate cortex (shown above) whereas conservatives had more gray matter in the amygdala. Both of these regions are involved in the cognition of emotion and may be reflective of the different levels of empathy and fear that go into the decision-making process during voting.

This is all well and good, but it doesn't alter the fact that a Hollywood actor finds it easier to get published than someone who has been in research for 3 years. I am not bitter. Honestly. I'm sure that once I am an established neuroscientist, I'll find it just as easy to break into Hollywood, won't I?


See: Political orientations are correlated with brain structure in young adults (Kanai et al., 2011. Current Biology)

Fruit fly may hold key to visual memory

Flies are a pain in the neck. Let's be honest, when the room is invaded by a big, buzzing intruder, the majority of us reach for the rolled-up newspaper. But few will realise that one of these aerial invaders has been at the centre of neuroscience research for many years. Because flies have a less complex nervous system than their mammalian counterparts, the common fruit fly (Drosophila melanogaster) has served as a useful model for studying the neural networks involved in behaviours that are observed in both humans and fruit flies (such as sensory perception and learning and memory.) 

In a recently published study, researchers from the Howard Hughes Medical Institute have used innovative techniques to demonstrate that the common fruit fly uses its vision to learn how to navigate (known as 'visual place learning'). As humans use the same process whilst navigating, understanding how organisms with less complex nervous systems achieve this form of learning may shed some light onto how humans do it also.

Researchers placed fruit flies in a small arena with walls that were under temperature control. All but one panel of the arena were kept at a temperature that was higher than would be comfortable for a fly to rest on. This meant that flies gradually made there way to the 'cool' panel after entering the arena. Surrounding the arena walls were visual cues such as crossed lines and parallel lines that the fly could use in order to orientate itself within its environment. After an initial phase, where flies entered the arena and made their way to the platform for the first time, flies were then taken out and then put back in and the time taken to find the 'cool' platform was measured. 

As the test phases progressed, flies got quicker at finding the 'cool' platform, which demonstrated that they had learnt where the platform was. Interestingly, when the platform and the visual cues were moved such that they were in the same relative position, flies still made their way to the 'cool' platform quicker than when they were first introduced into the arena. However, if the visual cues were not moved (and the platform was) or the flies were put into the arena in the dark, they failed to show any improvement in finding the 'cool' platform, suggesting that the flies were using their vision to learn the position of the platform.

Now, mammals are well known to be able to locate themselves in their surroundings using visual cues. In rodents, an area of the brain known as the hippocampus contains separate regions that encode different aspects of the spatial information. This is a fairly complex structure consisting of several integrated layers. What is fascinating about the current finding is that fruit flies have the ability to locate themselves in exactly the same manner, but do it with a much simpler nervous system. In fact, by actually repressing the ability of certain cells to work, the researchers were able to demonstrate that a small subregion of a part of the fly brain known as the central complex ellipsoid was all that was necessary for visual space learning.

This study has shown that the common fruit fly is a valuable tool in understanding visual learning and that further research using these winged beasts may reveal the systems that underly this process across a variety of different lifeforms. Perhaps the mammalian system is just a more complex version of the fruit fly system or maybe these two creatures have developed distinct solutions to a shared problem. It is likely that there is some truth in both of these propositions, but one thing is for certain, you should think twice before you next grab that newspaper, that fly knows how to find you!

See: Visual place learning in Drosophila melanogaster (Ofstad et al., 2011. Nature)

Welcome

There is nothing more fascinating than the mind. It is not only the most intricately complex structure known to man, but actually gives him the ability to know in the first place. It governs every decision we make and is influenced by every action we take. It is the integration unit for all that we perceive and all that we achieve. It is the centre of our very being and is the major determinant of the qualities that make each of us 'us'.

Whilst philosophers have pontificated on the mind for millennia, it is only relatively recently that scientists (from a wide range of disciplines but broadly known as 'neuroscientists') have begun to take serious strides in elucidating some of the mysteries of the mind. Great developments in mapping brain interconnectivity and the molecular machinery of the synapse have enormously improved our understanding of how the brain works, but there are still large questions that remain unanswered. What is the origin of consciousness? Do humans have free will? How do we formulate memories? What is a thought? To some extent these questions are philosophical in nature, but technological advances have allowed neuroscientists to take many philosophical questions into the realm of empirical scientific method.

This blog is an attempt to demystify a topic that might seem beyond many lay readers. Throughout my future posts, I hope to be able to convey some of the more important messages to emerge from neuroscience in recent times. I will often pay homage to some great early discoveries and talk to you about some of the people that are giving their lives to understanding what it means to be human. Neuroscience is a field as rich in diversity as the brain itself and it is my hope that this blog will be of use to lay readers and neuroscientists alike as I try to relay some of the most exciting discoveries of neuroscience in an easily digestible manner.


Ermerson Pugh once said "If the human brain were so simple that we could understand it, we would be so simple that we couldn't". Well, perhaps he's right, but let's have a bloody good go!