On the occasion of his participation in the XIII International Congress of Clinical Psychology (to be held from November 11 to 14, 2020, in Santiago de Compostela, Galicia, Spain), Wenceslao Peñate Castro (professor of psychology at the University of Laguna and vice president of the AEPC, Association organizer of the Congress) has carried out the interview that it reproduce below.

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First of all, Dr. Gonçalves, on behalf of the organization, I thank you for accepting the invitation to participate in the XIII International Congress of Clinical Psychology. We know how complicated your agenda is, shared with the management of departments and research centers in Europe and USA. As you know, the congress is going to be held from November 11 to 14 in Santiago de Compostela, a city that is not a stranger to you....

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Yes, indeed Wendi. It will be good to be back to Santiago, a place where I did my second doctorate with Professor Angel Carracedo at the Faculty of Medicine. As you know, there is a long historic connection between the Galicia and the North of Portugal and, in my lab, we maintain a close research collaboration with psychology and medicine at the University of Santiago de Compostela. Currently we have several excellent postdocs at our lab from Galicia – an outstanding group of young researchers trained by Fernando Diaz e Fernando Cadavera (“Fernando(s) Psychophysiology Golden Team”, as known among friends).  The past February we were honored to have Angel Carracedo, one of the world most famous geneticists, as the first honorary Doctorate in Psychology at the University of Minho (https://www.youtube.com/watch?v=DqH42_0MnFY). All in all, being in Santiago is like being at home, in terms of science, culture and friendships. 

 

Going directly into the theme of his lecture (Mini-Brains: Implications for Clinical Psychology and Ethical Considerations), the topic is as intriguing as it is stimulating. What does mini brains consist of?

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Brain organoids, known as mini-brains, are in vitro individualized 3-D models of the brain, derived from cultures of human pluripotent stem cells. Summarizing in few words what it is a complex technological process, we can say that mini-brains can be generated from an individual biological sample. From that sample, we can in the lab, induce pluripotent stem cells. During the course of several weeks, these progenitor cells give rise to neurons and later neuronal networks, recapitulating brain development.

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Does this mean they are 'representative' brains of the original brain, and, also, that they can accurately represent brain connectivity?

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These mini-brains are miniature models of the human brain, not real brains per se. A good metaphor is to state that brain organoids are for the human brain as a sophisticated train electric toy is for the actual train. Most of the structures and functions are there, but they are miniatures. The average 15 centimeters length of the human brain is miniaturized into a 4-mm-diameter size mini-brain, and 100 billion cells are reduced to 2 million mini-brain cells. However, it is important to note that mini-brain are able to express a diversity of brain regions (forebrain, midbrain, hindbrain) with already a rudimentary cortical differentiation into, for instance, sensorial and cortical regions. Madeline Lancaster published in Nature in 2013 the first paper describing how cerebral organoids can be effective in mimicking human brain development (https://www.nature.com/articles/nature12517). Since then, the field has increased in research sophistication combining the potentialities of self-organizing cultures with bioengineering tools in order to generate specific brain structures and modeling its functioning (https://www.nature.com/articles/nbt.3906).  After the initial technological sophistication, mini-brain research is moving fast to mimic brain structure and functioning in both, normal and abnormal conditions. 

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An important aspect, that is included in the title of your talk, are the ethical implications...

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The research is moving fast and the methods are increasing in sophistication, suggesting that mini-brains are able to establish self-organized patterns of activity. They seem to gain a life on their own; and because we are, in this case, talking about the brain, this life may be, in the limit, a psychological life. It may very well be the case that brain organoid researchers will start experiencing soon, the paradox of having found a dreaming tool that may turn into a nightmare. As in Mary Shelley’s novel, we may soon feel like in Dr. Victor Frankenstein experiment - creating a sapient but a hideous uncontrolled creature. This outstanding scientific advancement started already raising some ethical concerns among the scientific community - are we about developing a sentient organoid with not only sensory but also cognitive dimensions? Can brain organoids in the near future start evidencing consciousness? These are, indeed, important ethical questions that psychologists are called to address.  At the end of the day that’s up to us, up as psychologist,  to come with new methods to study if mini-brains have internal sentient states, and as such defining the potentialities and limits of cerebral organoid research.

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There are no doubts that mini-brains represent a very relevant advance in basic research. To what extent do you think neuropsychology and clinical psychology can benefit from this research resource?

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I believe that mini-brains are challenging the frontiers of clinical psychology research. Mini-brains are opening new windows for clinical psychology with the opportunity to study the system as well as cellular and molecular mechanisms associated with different psychological and brain disorders. We can find important breakthroughs already in mini-brain research modeling conditions such Autism Spectrum Disorders to Alzheimer’s Dementia.  The most interesting thing is that we can develop specific models within each disorder. For instance, in OCD, an area where I’ve been researching, it would be possible in the near future to come up with mini-brains clustered along different OCD subtypes (e.g., checkers, cleaners, hoarders, etc.) and to characterize them from the molecular to the system levels. We can even move further and develop individualized brain models for a specific patient. This would be instrumental in overcoming some of the limitations of our current psychiatry diagnostic systems and opening the door to design individualized treatments previously modeled in the organoid “dish”.  That is, mini-brains open the door for personalized treatments by modeling the mechanism of different clinical interventions and its effects on plasticity (e.g., epigenetic level) or regeneration (e.g., systems level). Of course, this would be more immediate for pharmacological intervention. However, given that we are progressively moving into proto-sentient mini-brains, psychologists are challenged to come up with “in vitro” models of psychological therapies. 

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Another subject within your interest of cognitive neuroscience is the use of Virtual Reality (VR), and its application in clinical setting. Could you tell us what your research group is working on in this regard?

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Exactly. Let me now briefly move from “in vitro” to “in virtuo” therapies. As you are guessing, there is a continuity in this process with the overall aim of moving into more science-based treatments. I believe that psychotherapy needs to move from just an empirical based approach to a science-based approach. Neuroimaging research from our team suggests that OCD difficulties in cognitive regulatory control result from an emotional imbalance between a hyperactive defensive system (e.g., threat) and a hypoactive appetitive system (e.g., pleasure). Clinically, were researching more effective ways for improving regulatory control (inhibitory/excitatory) while restoring the balance between the defensive and appetitive systems. In the process, we are developing a virtual reality (in virtuo) closed-loop human-machine interaction platform – NoOCD City - for improving autonomic and cognitive regulatory control in response to triggers of defensive (threat stimuli - inhibitory regulation) and appetitive systems (pleasant stimuli - excitatory regulation). NoOCD City was awarded in the 2018 Bial Award of Clinical Medicine and is now a top 10 finalists  in the Roche pharmaceutics’ Open Innovation competition - Building Tomorrow Together” (https://www.roche.pt/BuildingTomorrow/index.cfm/homepage/news/). 

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We are finishing. Now, I would like to know a little about your academic life, which is just as exciting as mini brains. You are often sharing your time in between Europe, USA, and Brazil, with stays at prestigious research centers and universities, where you direct  powerful departments in psychology. How do you cope with this intense “rhythm” of work?

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It has been both exciting and fun. I was led to move back and forth across continents very early in my career. In 1983 I got a Fulbright Award to pursue my Doctorate in the USA. I ended up graduating from the University of Massachusetts in Amherst.  Then took a faculty position at the University of California Santa Barbara when Michael Mahoney was still there. I moved back to Portugal, invited to help in launching a new psychology program at the University of Minho. In few years we went from being the “new kids” in the block to the top psychology program in Portugal. Along the way I decided to pursue my studies and went, first, to the Faculty of Sciences (University of Vigo) to complete a DEA in Biology- Neurosciences and later a Doctorate in Neurosciences at the Faculty of Medicine (University of Santiago de Compostela). In the process, I moved from clinical to clinical-neurosciences research establishing the Neuropsychophysiology Lab at the University of Minho (now “Psychological neurosciences lab”). Few years ago, I went back to USA as a chair of Applied Psychology at Northeastern University in Boston and holding a research position at Neuromodulation Center from the Spaulding Rehabilitation Hospital, Harvard Medical School. Now I’m back to Portugal, maintaining my research appointment in Boston and about doing a new move to another university and starting a new research program that will help in this translation from the bench (e.g., mini-brains) to the bed side (e.g., clinical treatments). These, Wendi, are just some snapshots illustrating what has been probably the central leitmotiv of my academic life – leading change and networking across cultures and knowledge domains – from in vivo, to in vitro and in virtuo contexts bringing together the clinic, science and technological advances. 

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And during this pandemic, how are you dealing with your other passion, as marathon man?

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As with everything … keep on running! As I learned from my friend Michael Mahoney “the objective of the dance is not to finish, but to dance!”

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That is all Dr. Gonçalves, it will be a special honor for us your participation at the congress. Thanks again for accepting the invitation and we are looking forward to your presentation. Enjoy your stay in Santiago.