Bruno Miranda is a Neurology resident physician in Santa Maria and has recently been in the news as one of the most promising physicians/researchers of the current scientific panorama. He has won the João Lobo Antunes Award from Santa Casa da Misericórdia, granted for the first time and intended to highlight resident physicians who are developing medical research projects, contributing to the advancement and improvement of patient humanization and treatment techniques. He is currently studying patients with Alzheimer's disease and other dementias, but to get to this continuity point he has been through many other houses in many other games. He is just about to start this research. Within perhaps two years he will have conclusions to present to the scientific community.
Our meeting point could not be any different than the halls of the Santa Maria Hospital, and after going up the never-ending flights of stairs to the Neurology department, we reach a library that holds hundreds of manuals and studies on the human brain. The brain, this dense and complex organ that so many incredible brains are trying to decode.
He studied at the Faculty of Medicine of the University of Lisbon (FMUL), participated in the Erasmus program that took him to Paris and spent some time in London at the end of his studies. It was in London that he decided to stay after finishing the sixth year of studies. He worked at the general medicine department for two years, but his heart beat the reasoning of his brain, which he so assertively studies and he returned to Portugal, where his wife had been. At Santa Maria, he goes back to general medicine for a year and dedicates the following eight months to Neurology. At this time, he took another break to complete his Doctorate degree, having enrolled in the Champalimaud Foundation doctorate program and returned to London to work on his thesis. Physiology and Cognition were his areas of expertise. “I was observing animals while performing a cognitive task and attempted to develop the Animal Learning Theory, which is also applicable to humans and is greatly connected with Decision Making”.
He then worked for three years on his project in London, only afterwards returning to Portugal where he dedicated a year to writing his thesis. The thesis brought together the learning theories and the possibility for “testing models, algorithms that are more common to the programming areas and that are used to optimize these same learning processes”. This complementarity of programming technologies and biology left him fascinated.
After all the changes and learning opportunities inherent to perfecting his professional standing, he returns to the Neurology residency at Santa Maria, where he has stayed until now. The thesis is complete and approved, and now he only needs to publish the work among the scientific community.
Arriving at Santa Maria was the necessary stop to bring together the academic experience and the clinical component to then substantiate his whole research.
He based his work on two very different learning methodologies: trial and error, and planning and projecting for the future.
“I studied how animals learn. One of the most accepted theories, the Theory of Learning by Reinforcement, states that there are two types of learning systems: one of trial and error, and a second that involves planning. Using a puzzle as an example, a person is able to build it without the general idea of the entirety of it, and through trial and error the person fits the pieces together and can even get some right (with a high enough number of attempts, the person would be able to complete it correctly). There is a different approach that implies a projection of how the puzzle will look once it's finished. This learning methodology requires making associations and having knowledge of the rules, making it a more complex and more evolved method from a phylogenetic point of view. Where extensive neurological work has already been done to support the trial and error learning methodology, the first steps are still being taken concerning this more complex process, where we try to work with more concrete hypotheses, but with still a lot of work to be done. It was following this latter learning methodology that I started my current project”.
This study is taking Bruno Miranda a step further, on making a connection between the learning process and memory. He intends to study two types of memory: episodic, which is related to past events, and semantic, with a higher cultural context and where the person learns, although not so related to personal experience, but more to living within a culture of imposed cultural rules.
This connection between learning and memory shows that the planning systems can be more complex, where “many defend that planning depends mostly on episodic memory. There are several authors defending that the memory of past events within a specific time and place context helps us project into the future. However, there are other types of projections that involve other domains or knowledge, which are not necessarily related to episodic experience. We have another type of memory, semantic memory, and it applies to various domains, e.g. motor, when we perform a gesture and this gesture is associated with a specific social message. If we apply this knowledge to a more clinical setting, i.e., people with deficiencies, with episodic memory area injuries, we know that they project themselves incorrectly into the future, but when asked about other events, namely cultural events, such as the country's current challenges, they will know what to answer in a very assertive manner”.
Are these types of memory, episodic and semantic, accommodated in different parts of our brain?
Yes. Episodic memory is known to be in the medial temporal lobe, mostly in the hippocampus area. Semantic memory is very multimodal, as it involves the integration of visual aspects, auditory aspects, etc. Although very little is known about it, especially concerning its location, semantic memory seems to be accommodated in the most anterior region of the temporal lobe. This proximity between the areas responsible for both types of memory is convenient, as both participate in different cognitive processes, namely planning.
If you were to perform a brain scan (magnetic resonance imaging) while performing a test on a patient by activating a type of memory, would you be able to read the most reactive area of the brain?
Yes, this is what is usually done, by creating tasks. It pertains to the area of functional imaging, an extensively used area in human research as it is conveniently non-invasive. The participants execute a task that intends to study a particular cognitive aspect while the magnetic resonance imaging is performed. There are studies that precisely demonstrate how certain zones of the hippocampus become active when people make a choice using old memory, always considering specific time and place contexts.
Other studies also demonstrate that if the task depends more on elements of semantic memory, the activity is greater on the anterior area of the temporal lobe. In this area of functional imaging, the interest or challenge for the researcher is often linked to developing a better task, since a more demanding task provides better results. Thought processes are very complex and involve several cognition domains. The more detail we seek on our study, the further we have to develop our tasks to create very specific choices, otherwise we are at risk of activating other areas and highlighting areas that are not at all related to the process being studied. And the conclusion is then dissolved. Nevertheless, this functional data can be complemented by injury data, neurophysiology data (electric records of the nervous system), and with experimentation in animals. When the study is well developed, e.g., when the neurophysiology records show that cells light up extensively in a certain area, when we put together these complementing aspects, the results of which are very compatible, then we have a greater certainty to say that a certain area of the brain reacts to a certain type of memory. And a simple misstep can contaminate the whole research.
How do you go from a study based on learning to the analysis of several types of dementia?
That is where I merged the experience of what I already knew with the clinical aspect of my day to day life. In truth, my patients are models of a process that is failing. And some of the hypotheses can be studied on these patients. On one hand, the clinical population is a test to verify our hypotheses. On the other hand, researching the most basic process can also make us look at the clinical reality in a different way. The physician must always look for a good explanation for the problems at hand.
Is dementia present after the failure of one single type of memory or must both types fail?
That is hard to know. Except for the cases of quick onset, the process of dementia is more related to neural degeneration. The processes fail slowly over time through neuronal loss. The particularity of this, which is very interesting, is that certain dementias occur more in certain cognitive areas than others. Some people are more fragile in certain areas of the brain, resulting in specific dementias, while others are more fragile in other areas, resulting in very different dementias. Dementia always results from a deterioration component, but it is also shown by a marking point in a person's life (e.g., being dependent of others). Only when one starts to show dependency upon others, are we facing an indicator of severity. Clinical deterioration is so strong that affects the person's daily routines. Cognitive deterioration can also be age-related. Let's compare it to a computer that becomes outdated, with old and obsolete processors that are no longer capable of running software.
Does this mean that if we exercise our memory and learning systems a lot we can revert the probable ageing of neurons?
There are several studies following this line of thought, but the major discussion is whether there is a cognitive reservation among people who have been through several years of education and trainings and have therefore demanded several domains of their brains. It is thought that these people have a type of protection, not from the process itself, but seem to stay more compensated for longer. These people use compensatory cognitive strategies, where if an area of the brain fails, the other areas will compensate for the area that failed. They are more capable of this because over the years they have developed the ability to make thought more flexible. This way, they are able to compensate for the affected areas with a greater ease, as opposed to never having behaved like this. But this topic is still very difficult to prove.
Within learning systems you always talk about patients projecting into the future. Is it the future that becomes damaged and the past that becomes more present, when you ask for memory recounts?
Memory is, in fact, lost over time, and there are several components of memory. But there are also memories that are very crystallised within the system and these are the older memories, the ones that were recalled more often. Therefore, what is lost is the ability to create new memories, and older memories are lost afterwards as a result of general failure.
There is also another point of view, in which memory can be useful for the things that a person does the most, which is passing time and planning the future. To give you an example, patients are not even capable of making shopping lists. Do you know why? Because they don't know what they will need them for. There is a failure of memory use that will solve the day to day problems. Dementias prevent projections into the future because the person no longer has memory to help in this process. But all of these are different views over a single topic that is not only related to memory but also to a lack of imagination and incapability to plan for the future.
You won the João Lobo Antunes Award, granted by Santa Casa, as a wager on something that you are only now starting to develop…
It works as a scholarship, despite being called Award for its curricular assessment. I'm proposing to study both memories, episodic and semantic and their role in planning. On one hand I'll be working with Alzheimer patients, as their main issue is the failure of episodic memory. On the hand, there is a rare semantic dementia where patients show difficulty precisely in aspects related to semantic memory. We then have two models to test the hypothesis of whether these two types of memory contribute, in fact, for planning into the future. There is a lot of information on how episodic memory helps the person's projection into the future, but there is very little information related to semantic memory because it is assessed as subjective, as there is no good way of measuring it. What did I do? I created tasks for both episodic and semantic memory. These tasks are very similar. Concerning episodic memory, the person plans what to do next. Concerning semantic memory, the person depends on something that is known, agreed upon. What do I want to test? I want to see if patients with initial signs of Alzheimer - as later they will not be able to cooperate much in these tasks - are failing more in the episodic tasks, but perform semantic tasks relatively well. And the opposite with semantic.
The test of this hypothesis is positive since from there we can push the boundaries further. As these are two types of different dementia, if the tasks are capable of showing a distinction, it will show that one circuit is more affected than other. In a practical application for medicine, this allows us to approach patients in a different and more precocious manner. Where basic research is concerned, it can demonstrate through more objective assessments that, maybe, planning really depends on both of these memories. At this stage I can already send out a challenge for students of Medicine, as they can work with me in this research, but also by exploring new aspects and by developing their Master's thesis, as can be seen by my cooperation with a student in a scholarship from GAPIC. I am available to welcome and accompany them.