In the previous edition of Think, Professor Giuseppe DiGiovanni announced the launch of the Malta Neuroscience Network. The group has now had its first public seminar that attracted neuroscientists, neurologists, psychologists and psychiatrists. It consisted of two talks by world-renowned researchers.
Interdisciplinary research and practices blur boundaries. While the premodern approach to research distils areas into fine categories and certainties, interdisciplinary ideas spread across different fields. Performance is charged with interdisciplinarity.The University of Malta’s School of Performing Arts conducts interdisciplinary research that connects the performing arts with various disciplines in the Sciences and Humanities. This year’s school annual conference focused on this, in particular on eight overlapping performance categories: everyday life, the arts, sports, business, technology, sex, ritual, and play. The performing arts can endlessly combine these groupings in ways that range from theatre, dance, and music, drawing material from—but also impinging upon—everyday life, to training in performance and in sports. These arts share the drive for efficacy and efficiency with business, besides witnessing an increasing use of technological innovation.Continue reading
Creativity is a quality that we, as humans, think is ours alone. Prof. Georgios N. Yannakakis is creating computers that might have already taken this away from us. Computational creativity is here. His games are helping children be more creative, others to overcome dyslexia, and even combat bullying. Words by Dr Edward Duca.
When Mike* went to the nursing home that evening to visit his grandmother Maria*, she was worried that he wouldn’t be able to find her because the caretakers had changed her room. Mike tried explaining to her that her room on the 4th floor had been refurbished a year ago, but she couldn’t remember.
‘Can life without memory be considered a meaningful existence?’ asks Dr Charles Scerri (Malta Dementia Society, and Department of Pathology, University of Malta). Dr Scerri researches dementia. He is currently examining which physical environments and what sort of psychosocial wellbeing can improve life in local dementia hospital wards. In fact, Dr Scerri reports that today there are over 44 million people suffering from some form of dementia. That is around 100 times the Maltese population. He asks, ‘what type of society can we end up with if we are wholly made up of individuals with no past and an uncertain future?’
With more people relying on new media technology to record information and experiences, Dr Scerri’s question faces a future society where media could replace memory. ‘It would be short-sighted to think that new media will have no long-term influence on the complex nexus of personal and cultural memory’, says Dr James Corby (Department of English, UoM).
Photography already acts as a surrogate for memory. But, it does not stop there; theorist Roland Barthes goes one step further saying how photography can capture details missed by the human eye. As developers of new media strive to enhance experiences, more users are adopting them. In the final quarter of 2012 alone, Apple sold 37.4 million iPhones. This smartphone, equipped with HD video, an in-built camera, calendar, and interactive 3D map helps people capture memories and avoid having to remember appointments or directions. It even comes with Siri, your own ‘personal assistant’, to use Apple’s words.
Despite these abilities, Dr Corby is sceptical. As a researcher working on the interfaces between literature, philosophy and culture, Dr Corby thinks that the rich tradition of the humanities should inform debates about cultural memory. ‘The idea that a facility to record memories leads to the diminishment of personal memory is by no means a new idea. Indeed, it is precisely the accusation that, in Plato’s Phaedrus, Socrates makes against writing.’ Writing did not steal our ability to remember and neither should new technologies.
“You can never really know if what she’s saying is true because her memories are not always real”
So what would happen if old or new media failed us? When the accounts office of the family business burned down, Mike could relate to his grandmother’s anxiety due to her lack of personal memory. All the accounting records, invoices, transaction records, and overseas payments were destroyed. The accountant was so shocked that he still will not enter his old office after 15 years.
The accountant had to keep paper records. There was too much information to remember and they couldn’t memorise it all. Although they recorded the information they still lost it in the fire.
| More about Alzheimer’s in Malta |
 Dr Scerri has collaborated with the Department of Pathology to launch the Alzheimer’s Disease Research Group (University of Malta). Their objective is to gather several multidisciplinary professionals to ‘promote and facilitate research and scientific collaboration in Alzheimer’s disease and other forms of dementia’. Together with Trevor Zahra, he recently released the publication X’ħin hu? Fatti dwar id-dimensja (What time is it? Facts about dementia). |
We all risk losing both valuable information and the recollection of experiences. So what would happen if Malta became a nation of people without a memory of important events? For Dr Corby, a society which relies on new media and less on memory ‘might then lead to a complete eliding of any difference between personal memory and an increasingly undifferentiated surfeit of readily available cultural memory — a sort of technologised and globalised cultural eidetic memory’.
There’s also the possibility that media such as photographs could lead to the creation of cultural memories which never took place. ‘I imagine false memory to be the norm—it would be naïve to think that the visual representation of a culture […] is free from ideology’ says Dr Corby. Our national identity will instead be formed around uncertain events.
Joe Rosenthal’s photograph of American soldiers raising the American flag on Mount Suribachi on the island of Iwo Jima signifies a moment of national pride for Americans. Few Americans are aware that the photograph shows the flag being raised for a second time. The first flag was too small but the second larger flag would be seen by incoming ships.
Similarly, on the 4th floor of a nursing home, an old woman recalls how the nurses refused to take down the Christmas decorations. In her room, there was only a lone poppy. ‘She often creates stories in her head’, says Mike. ‘You can never really know if what she’s saying is true because her memories are not always real.’
‘Memories are created by altering a set of connections between brain cells so that one cell stimulates the others,’ says Jonah Lehrer, Wired Magazine. By creating memories, we are literally rewiring our brains. Every time a memory is recalled, the connection between brain cells is restructured and the memory altered depending on the stimuli of the current situation. This means that whilst media may fail us, so might our memories.
Will a nation inevitably make the same mistakes because its people cannot remember past experiences or because they replace them with false ones? When asked how memory recall can be assisted, Dr Scerri acknowledges that media is a useful tool in improving memory, as ‘memory albums are extremely valuable for individuals with dementia in facilitating memory events and in reducing anxiety and confusion’. Perhaps these tools can help Mike’s grandmother.
*Names have been changed to protect the identity of the people mentioned in the article.
Giulia Bugeja is part of the Department of English Master of Arts programme.
Look out for an in-depth feature on dementia in the next issue.
In the 1960s, psychologists Roger Sperry and Michael Gazzaniga performed experiments on patients who had the connections between the left and right side of the brain cut as an extreme treatment for epilepsy. They stimulated each side of the brain separately and asked patients to draw, arrange blocks, talk about their emotions, and so on. These simple experiments proved insightful but misguided.
From their experiments they concluded that the left hemisphere was logical, rational, and good with numbers (the scientist), the right hemisphere was creative, imaginative, and took in the big picture (the artist). This overly simplistic reasoning is drowning out the real beauty of our brain. The real deal is a lot more complex. Take speech. Classically, the left side of the brain is meant to handle it all. Right-handed people do mostly use the left side, but left-handed people tend to use the right side. Imaging studies of brains show that the brain lights up like a firefly using multiple areas for speech. Most complex actions need multiple brain areas.
The winter rays of sunlight reflected off the snow upon Mount Maiella and the beautiful Adriatic Sea. They lit up the room where I was sitting with Dr Ennio Esposito (head of the Neurophysiology unit, Mario Negri Sud, Italy). On this cold day in February the light was blinding and it was difficult to make out my long time friend and colleague. Together we had studied the brain chemicals serotonin and dopamine vital for love, pleasure, addiction, and linked to depression — my research subject.
‘Ennio, I am tired and frustrated, I am increasingly convinced that our in vivo (whole organism) experimental approach is not the right one. There is too much variability in the results and if we really want to understand the cause of depression and find a new cure we need to get some reproducible data and change our tactic.’
“We still do not understand how many psychoactive drugs actually work, meaning that more research is needed”
At that time, I was using glass electrodes to study changes in the electrical activity of single neurons in brains. Additionally, I used a technique (microiontophoresis) that registers neuron electrical activity and also applies a very small amount of the drug. In this way, I could see which brain cell was active and how different chemicals might influence it. Surprisingly, though introduced in the 1950s, these techniques are still some of the best ways to study drug effects on a living brain.
My research focuses on the role of two brain chemicals, dopamine and serotonin, in mental disorders. When stimulated neurons release chemicals (neurotransmitters). I am interested in dopaminergic neurons which release dopamine and serotonergic neurons that release serotonin. Once released, chemicals can pass through the spaces in between neurons and bind to another neuron stimulating or inhibiting it. They bind on proteins called receptors. When they do, they trigger the cell to fire or shut down. By triggering certain neurons in our brains, they reinforce or change our behaviour.
Dopamine is involved in the pleasure pathway. It switches on for behaviours like emotional responses, locomotion, and reinforcing good feelings. Changes in the level of dopamine effect a person’s reward and curiosity-seeking behaviour, like sex and addictive drugs. On the other hand, serotonin seems to have a more subtle role. One of serotonin’s major roles is to modulate or control the effects of other neurotransmitters, such as dopamine. In the words of Carew, a Yale researcher, ‘Serotonin is only one of the molecules in the orchestra. But rather than being the trumpet or the cello player, it’s the band leader who choreographs the output of the brain.’ The belief that serotonin is the brain’s ‘happy chemical’, that low serotonin levels cause depression and antidepressants work by boosting it is a very simplistic view. In truth, no one knows exactly how dopamine and serotonin levels induce depression.
“I have spent my life trying to figure out the role of dopamine and serotonin in the brain”
A lot of what we do know is because of animal research. The animals used to model this disease are given antidepressants to try and understand how effective they are and how they work. By studying their brains we can start to comprehend what causes depression. Right now we do not understand the whole picture behind the causes of depression and patients end up receiving inadequate treatment. We still do not understand how many psychoactive drugs actually work, meaning that more research is needed.
Most drugs were discovered by chance while being used to treat other disorders. For example, the antidepressant Iproniazid was originally developed to fight tuberculosis.
After the researchers saw less depression in patients suffering from tuberculosis they started prescribing it to depressed patients. In another example from the 1950s, clinicians discovered the first tricyclic antidepressant while searching for new drugs against other mental diseases.
Today, we fortunately have a battery of drugs that can treat depression. Unfortunately, the best drugs on the market only completely alleviate symptoms in 35 to 40 percent of patients compared to 15 to 20 percent taking a placebo (a sugar pill), a fact not publicised in pharmaceutical ads. Another problem is that when people begin taking antidepressants, mood changes can take four weeks or more to appear. This delay in action is one of the major limitations of these medications since it prolongs the impairments associated with depression, increases the risk of suicide, the probability that a patient stops treatment, and medical costs. To tackle these problems pharmaceutical companies and academic researchers want to find more effective and faster acting antidepressant drugs.
Ennio and I, together with Vincenzo Di Matteo and other researchers at the Mario Negri have tried to resolve the antidepressant lag time enigma by studying rats. We first inhibited the levels of serotonin for 3 weeks using the latest Selective Serotonin Reuptake Inhibitors (SSRIs) named fluoxetine, sertraline, and citalopram. Then we measured the electrical activity of dopamine and serotonin neurons in rat brains. We discovered that the therapeutic effect of antidepressants is not only due to their capacity to restore a normal level of serotonin activity. It also induces adaptive mechanisms in the dopaminergic system (that releases dopamine) because of repeated treatment.
How do SSRI’s treat depression? At first, these chemicals only slightly stimulate serotonin release. Long-term treatment kicks in an adaptive process. The receptor type located on serotonergic neurons which inhibit serotonin activity become insensitive. Repeated treatment frees serotonin neurons from this ‘brake’. By repeatedly using these drugs (with a lag time of 2–8 weeks), the levels of serotonin being transmitted increase and stay high for a longer time which is responsible for the SSRIs antidepressive effect.
The perfect antidepressant could lie in blocking the activity of these receptors since there would be no major delay in action. This hypothesis was confirmed by Francesc Artigas and his research group (University of Barcelona). They administered pindololo, a drug capable of blocking these serotonin receptors, and observed an increase of the antidepressive effect of the drugs paroxetine and fluvoxamine. They worked by reducing the latency period. Patients on pindololo did noticeably better and the clinical data matched that from laboratory animals. Blocking this type of serotonin receptors can be a promising therapy to reduce the latency period and possibly, increase antidepressant action.
My colleagues and I formed an alternative hypothesis as to why the clinical effects of drugs are delayed for so long focusing our attention on the dopaminergic system. We showed that acute administration of different SSRIs reduces the electrical activity of dopaminergic neurons, which release dopamine. These drugs increase the levels of serotonin, which decrease dopaminergic neuronal activity (which release dopamine) by over stimulating another inhibitory serotonin receptor this time located on dopaminergic cells. The result? The drugs taken to cure depression paradoxically initially induce a reduction of dopamine, which is meant to be the neurotransmitter of well-being and happiness! Indeed, SSRIs can worsen the depression of patients in the first few weeks of treatment.
When the drugs are used over a long period of time (3–4 weeks), the initial reduction of dopamine reverses. The change happens because the repeated treatment reduces the sensitivity of this type of serotonin receptor on dopaminergic cells freeing them from their serotonin ‘brake’.
“All of our work has made it possible to consider new treatments of depression”
We think we have found the reason why SSRI antidepressants take so long to work. Two different serotonin receptors need to become insensitive to the level of serotonin in the brain, one found on serotonergic cells, the other on dopaminergic cells. Their insensitivity allows the activity of dopaminergic neurons to return to normal even though the serotonin activity has been bumped up.
Other labs have confirmed our results, which is vital step for a theory to become fact. Cremer and his team (University of Groningen, Netherlands) have shown that blocking the same type of serotonin receptor on dopaminergic cells in rats can improve the effect of SSRIs antidepressants. Ultimately all of our work has made it possible to consider new treatments of depression, which I am very happy to see.
Many questions remain unanswered about depression. The most urgent task is to find a more effective way to treat it. This is my goal, I have spent my life trying to figure out the role of dopamine and serotonin in the brain — with some notable successes. I hope to see the next generation of antidepressants which would improve the life of 121 million depression sufferers.
Ennio listened to me as I expressed my frustration after once again obtaining conflicting results in the laboratory. ‘Giuseppe’ he said ‘You are right, billions of neurons in our brain behave differently, but as Douglas Adams said, ‘If you try and take a cat apart to see how it works, the first thing you have on your hands is a nonworking cat. Life is a level of complexity that almost lies outside our vision’ (Hitchhikers Guide to the Galaxy). If we want to break the code of the brain and hope to treat its diseases we need to take a holistic approach that takes the whole brain into account.
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Article dedicated to the prominent researcher Dr Ennio Esposito, Prof. Di Giovanni’s (Department of Physiology and Biochemistry, UoM) colleague and friend. In 2011, he died of a heart attack. During his last years, he suffered from a severe refractory bipolar depression. If interested in an M.Sc. or Ph.D. in biological psychiatry please contact Prof. Giuseppe Di Giovanni
TED talk about targeted psychiatric medications, similarly to Prof. Digiovanni borne on the realisation that current treatments are not good enough for everyone