OHBM 2022 Talairach Interview with Professor Andreas Lozano

Rahul Gaurav

Movement, Investigations and Therapeutics (MOV'IT) team and the Center for NeuroImaging Research (CENIR) at the Paris Brain Institute (ICM - Institut du Cerveau), Sorbonne Université, INSERM U1127, CNRS UMR 7225, Pitié-Salpêtrière Hospital, France. 

Dr Lozano is a neurosurgeon and University Professor at the University of Toronto, where he is best known for his work in the field of Deep Brain Stimulation (DBS) and Magnetic Resonance-guided Focused Ultrasound (MRgFUS).  His team has mapped cortical and subcortical circuits in the human brain and has advanced novel treatments for Parkinson’s disease and for depression, dystonia, anorexia, Huntington’s, and Alzheimer’s disease. Dr. Lozano has over 750 publications and serves on the boards of several international organizations. He has trained over 70 international postdoctoral fellows. He has received a number of honors including Doctor Honoris Causa from the University of Sevilla, the Olivecrona Medal, the Pioneer in Medicine Award, and the Dandy Medal. He has been elected to the Royal Society of Canada, has received the Order of Spain, and is an Officer of the Order of Canada. Here, he sits down to discuss his work and his OHBM2022 Talairach address.

Rahul Gaurav (RG).  Welcome Professor Lozano! It is an absolute honor to have you here. Thank you very much for your time. Could you tell us where you started your early career?

Andreas Lozano (AL). Thank you very much. As a teenager, I became interested in the brain while watching a TV program on Dr. Wilder Penfield from Canada. Then I realized that the best way of doing this is by becoming a Neurosurgeon. Later, I got accepted to the Montreal Neurological Institute where Dr. Penfield worked.

RG. Did you start in Canada or in Europe?

AL. I started in Canada. I was born in Spain, but my family came to Canada when I was a child. I grew up in Ottawa, went to medical school in Ottawa, and then transferred to McGill University where I did minor surgical training and a PhD in neuroscience.

RG. Tell us about the obstacles you faced at the beginning of your career. Did you have supportive mentors, role models, etc.?

AL. I had some historical role models, and—being Spanish—I was particularly fond of Santiago Ramón y Cajal who won the Nobel Prize in 1906. Dr. Penfield was a role model as well. I directly worked with the neurologist Professor Marsden, and I worked with Professor Tasker who was a neurosurgeon involved in brain mapping.

RG. What do you think about your most important contribution in the field?

AL. I think we've contributed in two ways—and this is not an individual contribution, but rather a group of scientists, students and fellows. The first one is in brain mapping. So, in the course of doing neurosurgical interventions, we've been able to go through areas in the brain where no one else has gone before. We were able to obtain direct measures of neuronal activity in these areas, and we were able to discover the nature of the neurons, what kind of behavior they had, and their spontaneous activity. By stimulating them, we also gained some insight into what those areas of the brain do.

The second one is in clinical practice, probing various circuits in the brain with deep brain stimulation (DBS) to see whether DBS can provide some therapeutic benefits. We started off with DBS for pain. Actually, that was the first indication back in the 1970s. I got into DBS in the 1990s and then moved to movement disorders, and then to psychiatric disorders like depression. So going to areas of the brain that were relatively unexplored, interrogating the neurons by stimulating them, and then seeing what these areas of the brain are doing.

RG. Recently, there have been various attempts in developing MRI biomarkers to provide an early diagnosis of the disease. What do you think could become a reliable future biomarker?

AL. My hope is that we develop a marker to image alpha-synuclein. In Alzheimer's disease, we have the beta-amyloid markers that have been effective in understanding the pathophysiology, and the progress of the illness and also has acted as a therapeutic biomarker. I think that we're not there yet in Parkinson's disease (PD). We know that there's an alpha-synuclein accumulation in the brain in patients with PD, but we have no way of imaging this. We can image dopamine deficiency in various ways, which is helpful. But I think we really need a molecular biomarker; I think we're behind in the molecular biology of PD compared to Alzheimer's.

On the other hand, I think we're further ahead in the circuitry of PD and the dysfunction in the circuitry, and this is why we have therapeutic strategies in surgery and modifying the activity of circuitry. There are some imaging correlates of that, too.

RG. Here in our movement disorders team at ICM - Paris Brain Institute, we have been focusing on neuromelanin MRI as a surrogate marker of dopaminergic neurons using AI. What is your take on this?

AL. Yes, I think it's a great marker. The issue with PD is that it is a multi-system, multi-transmitter disease, and it goes beyond the dopaminergic system. We realized that there was tremendous cholinergic innervation as well in PD; there’s a tremendous degeneration of the pedunculopontine nucleus, which is involved in gait. I know that in ICM - Paris, there's an interest in this nucleus.

I think that PD goes beyond dopamine, and we are getting better at treating the dopamine deficiency aspects of PD, but we are not very good at treating the non-motor, non-dopaminergic aspects. We have patients with DBS, for example, who have been treated 10–20 years ago, who are doing reasonably well from a motor standpoint—they don't have tremor or rigidity, and so on—but they're becoming demented: they can't stand they can't walk; they can't swallow. These are problems that are outside of the dopamine system and do not respond to dopamine replacement.

RG. It's interesting that you mention the non-motor aspect of the disease. Do you think that artificial intelligence (AI) could be a game-changer in the future for finding the cure?

AL. It's hard to predict how important that will be, but it is certainly extremely promising.

We are actually using this approach of AI to set up our patients with DBS. We are looking for biological markers that we have engaged the appropriate circuits and that we are creating the necessary changes in the activity of those circuits to produce the optimal clinical benefit. So we feel that there are biological markers of success in DBS, and we are now using those markers as the endpoint of programming.

Rather than using a trial and error of the neurologist, trying the DBS setting and then waiting is critically important, because the responses are often delayed by several days or weeks. One cannot rely on an immediate response—not just in PD but also in dystonia or depression, where it takes weeks or months to get a response. We cannot expect an immediate biological effect. So instead, we're trying to use AI to stimulate by looking at what areas are affected in the brain, what is the magnitude and direction of the changes and using that to program our DBS setting. AI may play a very important role in the future.

RG. Which is the more important motor or non-motor aspect in PD? Do you think enough attention has been paid in recent years to the non-motor side?

AL. I think it's important to stress that these are illnesses that evolve over time and that initially, motor symptoms are the dominant features of the illness. As the disease progresses, there are treatments for the motor system problems but not so much for the non-motor symptoms; in particular, for dementia. If you follow patients with PD for 20 years, 80 to 90% of them will have cognitive disturbances and dementia despite any medication, despite DBS.

This is what we're facing now: we've developed strategies to treat motor problems that are of some effectiveness—not totally effective, but some somewhat effective—but now, the great burden is that we are dealing with other, non-motor problems. So, for us, that is now becoming the dominant problem in our patients. It's like playing the game of Whack-a-Mole where you deal with one problem, but then another one emerges. Now the problem that is emerging in our patients is the non-dopamine aspects of the illness.

RG. Which one would you rate the most important aspect of the disease?

AL. The patients tell us that the most disabling things are their depression, gait, mood, and probably cognitive function. I’d say their mood and their gait are the most important problems in the chronic form of the illness—as well as gait where they simply cannot walk properly. So, these are ones where we have to understand what the neural substrates of these problems are. What is the pathophysiology? What is going wrong in the brain? If we understand that, then we'll be in a position to develop better treatments for these problems.

RG. As a surgeon, what about the aspect of dopaminergic neurons in substantia nigra? Have there been any studies on how to deal with it from a surgical point of view?

AL. Well, there are approaches, but so far we have nothing to protect these neurons from dying. There have been a number of neuroprotective strategies that have been tried, but none of them have been successful—including gene therapy.

The other approach has been to transplant neurons in the brain, and we and others are currently in a study of transplanting stem cells to the putamen. These are stem cells that are differentiated towards expressing a dopaminergic neuron phenotype. We are transplanting 2.7 million of the cells into the putamens of patients with PD in the hope to replenish the dopaminergic integration of the putamen. So, that is a second strategy that has been used to try to deal with these missing dopaminergic neurons.

We realize that dopamine is only part of the picture, not the entire picture. So, I think that it will be a symptomatic therapy, but it will not be a curative therapy.

RG. What is the precision of these methods?

AL. These results are still early on.

Historically, there were fetal cell transplants which were done in randomized trials. These have not proved to be effective, and they were shown to cause some significant adverse effects; for example, the so-called runaway dyskinesias. We are now trying to transplant a homogeneous population of cells. That's where the stem cells come in: you can grow millions of cells and have a homogeneous set of controlled cells. Hopefully, we'll soon be in a position to ascertain whether this could be safe and useful in patients with PD.

RG. Using the expertise of both brain mapping scientists and surgeons, do you think we could really find a cure?

AL. I think a cure is optimistic and would have to rely on some form of genetic intervention. For example, if you are a parkin mutation (heterozygote, homozygote etc.), I could envisage doing gene therapy to reimplant good copies of the gene. That would constitute a cure if you're able to completely reverse the pathogenesis of the illness. So, in the genetic forms, I think that there's a possibility of a cure.

The so-called sporadic forms are much more complex, because we don't understand why these people are getting the symptoms. But if we are able to pinpoint the circuitry better and then have very localized approaches within that circuit, then we could do better. As surgeons: we can go absolutely anywhere in the brain; there isn't a neuron that is safe from a neurosurgeon. We can deliver anything almost anywhere in the brain, and in the future, we'll be able to use more noninvasive therapies to deliver to our targets.

For example, the use of focused ultrasound: where one can open the blood-brain barrier focally and then inject either nanoparticles or viruses etc, to give proteins or to administer gene therapy in a so-called noninvasive way, without having to open the skull. The idea is that you open the blood-brain barrier in a specific location and you deliver the therapy intravenously, and it would only enter the brain where the blood-brain barrier was open. In this way, you could deliver proteins—or antibodies or gene therapy—to a focal area of the brain without having to open the skull. These experiments are underway, and I think show considerable promise for the future.

RG. Do you think that high-intensity focused ultrasound could play an important role in the symptomatic treatment of PD?

AL. Yes, there are really three different approaches. One approach is to use high-intensity focused ultrasound to make lesions in the brain to perform e.g. pallidotomy to treat tremors. Secondly, it is possible to use ultrasound to stimulate the brain. One of the properties of ultrasound is that the focal point is quite deep and can go 8cm in the brain. So, you can reach quite deep targets in the brain with ultrasound; we'll see whether that's useful for PD. The final approach is possible to open the blood-brain barrier via focused ultrasound, opening the blood-brain barrier and to intraveneously deliver therapeutic agents to the brain.

RG. What about other non-invasive techniques? Do you think that TMS or another device could be helpful as well?

AL. Yes, but there's not yet been a breakthrough in my opinion in TMS for PD, as it's not used and it's not approved for PD. So, the effects are relatively minor. One of the issues is that TMS is applied intermittently and has an issue of specificity. It is not a continuous therapy like DBS which is 24/7. I think much more work needs to be done: not just in TMS, but in other forms of noninvasive therapy.

RG. You're one of the few researchers who have described the neurophysiology of the subthalamic nucleus (STN) in the past. Could you enlighten us about that?

AL. When we started to do DBS for the STN, we had the opportunity to discover what these neurons are doing. I think our group was the first one to publish the neurophysiology of the human subthalamic nucleus neurons. We were able to record these neurons and describe their physiology, receptive fields, their responses to movement. We were also able to do interesting experiments to hold individual neurons in PD patients. These neurons have very fast firing bursting characteristics. We were able to administer apomorphine while the patient was being operated on and recorded the same neuron showing that the apomorphine actually changes the activity of these neurons. The neurons slow down, they become more focused in the receptive fields. Less bursting, etc. We were able to get some insights into what happens in the context of dopamine denervation in the dopamine deficiency state, the abnormal activity of the STN, and then as you restore dopamine, how these neurons shift to firing in a more normal way. We were able to do this by recording seal neurons in the operating room. This was a useful insight into the pathophysiology of PD and how levodopa exerts its mechanism of action.

RG. How do you use the DBS on PD? Is it a long procedure?

AL. We do 2-3 DBS procedures per week. The actual DBS surgery takes up to 2 hours. We are down to 2 hours to map the STN and implant the electrodes. It has become a routine procedure. It has been estimated that over 200,000 people in the world have received DBS for PD.

RG. Can the patient go back to work or live a normal life the next day after the procedure?

AL. Yes, it depends on what kind of shape they start off with. If you have a patient who is young, who's relatively in good shape, who's the same advice, a tremor or with motor fluctuations, and DBS is very effective for motor fluctuations and for tremor, so if that patient is working, the idea is to operate on them before they lose their job and to keep them in the workplace longer. We hope that by introducing surgery earlier we can remove some of the opportunity costs associated with having PD and people can stay active and be more ambitious and reach their goals. The surgery will hopefully allow them to do that.

RG. What do you think about non-pharmacological interventions in PD like exercises, yoga, etc.?

AL. Mood and health are crucial aspects of the illness and we have patients who are very disabled and yet are content and functioning with a quality of life that is better because of their mood, and exercise. These things have a direct protective measure and a direct symptomatic benefit.

RG. My last questions are more focused on young trainees and early career researchers. What advice would you give those who would like to follow a path similar to yours?

AL. Curiosity is very important, and latch on to a problem that you can devote your career to, and something that is unlikely to be solved in your career. For example, unraveling what causes PD and coming up with new treatments would fall in that category. Drive and determination are very important. The ability to persevere and to overcome obstacles is ultimately what will determine what will make the difference between success and non-success. Also, surround yourself with excellent people. These are team sports, and you have to be in an environment of people that will challenge you and motivate you. Choose an environment where these important needs can be met.

RG. A big difficulty for people to handle is the work-life balance. What is your advice on the integration of work and life?

AL. It's not how much you work but how you work. It has to do with the quality of how you spend your time and that's where the work balance comes in. A different mind can always be in the same state. It's important to be able to do other things, such as family, friends, exercise, etc. This will help prepare you for your work. Everyone has to find their own inflection points in this. You have a paper that you have to get in where you devote 100% of your waking time to your research, and there's no time for anything else. You have to also incorporate these periods of high-intensity activity. But after that's finished, you need to recharge and reconnect with other activities.

RG. Speaking of taking one challenge at a time and working on that challenge, do you think it's wise to stick to one problem or to have several related problems throughout the career to advance?

AL. Well, my feeling is that you should have a theme. If you pick PD, there are many sub-problems within that and you need to have a diversified portfolio because most of your ideas will not work. Linus Pauling said that the way to have good ideas is to have a lot of ideas. You have a lot of ideas, realizing that the majority of them will not work out but if 10-20% of them do work out, then that is enough. All you need is one really good one. My advice is to have many ideas and to pursue them. There will be some winners and losers among those ideas and dump the losers and just focus on the winners. There will be many things that do not work and you start off your career with one idea and you often end up somewhere completely different. That's because you follow the logic of the science and the discoveries as you go along.

RG. That's quite inspirational. For the last point, would you like to add something else focused on our human brain mapping community?

AL. It's a great opportunity to convene people from different fields. I think that's where the excitement is where you can tackle a problem from multiple different approaches, and have engineers, imaging scientists, biologists, radiologists, clinicians, etc. in the same venue in the same format. We will be able to accomplish much more than working individually. Hopefully, we will come together and push the frontier of neuroimaging and neuroscience even further.

RG. Thank you very much Professor for your time. It was an absolute pleasure.

AL. Thank you very much for your time.