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'This is not science fiction'

Transcript from June, 2020

Localisationism is dead. That’s no surprise of course, given that the concept of neural plasticity has been ‘on trend’ since my undergraduate science days, and for good reason. In the last decade or two, research has continued to describe the ‘plastic’ functional reorganisation of the brain based on neuro-imaging studies, lesional studies and a-priori brain mapping studies conducted during awake brain surgery. In short, under certain circumstances the brain is capable of adaptation if damaged.

Localisationism refers to the idea that distinctive portions or areas of the brain are responsible for individual functions, a concept that has been explored for millennia. The oldest documented description of the brain was in hieroglyphic-form in the Edwin Smith Papyrus (c1700BC), and yet the earliest reports of the brain holding some degree of meaningful importance dates back to the era of Vesalius (c1500AD). In its crudest form, concepts of localizationism can be traced back to the study of phrenology in the 1700s, where conformations of the skull represented various cognitive faculties and behavioural traits. Having swiftly been discredited by scientific research, and sometimes referred to ‘how not to do science’, it would be remiss not to recognise that one of the five principles of the practice of phrenology recognised that the brain was the ‘organ of the mind’.

Professor Hugues Duffau is chairman of neurosurgery at the Montpellier University Medical Center in France. He is also a clinical neuroscience PhD, and a highly regarded expert in the surgical management of slow growing (lower grade) brain tumours using comprehensive cognitive mapping with electrical stimulation during surgery. Whilst there are a great many neurosurgeons specialising in awake brain surgery internationally, Duffau has spent two decades treating patients assisted with complex brain mapping to gather data and publish research that share a common theme: that the next decade of brain mapping will depend upon neurosurgeons to challenge the tenets regarding brain function. “Localisationism does not exist in the central nervous system, this is only a dogma”.

Awake brain surgery is probably a horrifying idea to the uninitiated. However in circumstances where tumours grow near areas of the brain that mediate ‘eloquent’ function — such as speech, language, movement and sensation — oftentimes an awake approach permits the greatest chance at avoiding these areas during removal of the tumour, because the patient is responding in real-time to the surgical team and also in response to direct electrical stimulation of the brain to ensure that these functions remain uncompromised. Any evidence of functional localisation matters greatly during these procedures so that eloquent regions of the brain are avoided, lest the patient experience debilitating neurologic consequences post-operatively.

To further complicate matters, pathologic grading of primary hemispheric brain tumours can impact the patient’s post-operative course. ‘Lower grade’ tumours grow at a lesser rate than ‘higher grade’ tumours, but surgical approaches can vary given the degree of infiltration, access to appropriate surgical treatment centres, and location of lesions. When it comes to electrically mapping these areas during surgery, there are also noticeable differences in approaches, techniques, and philosophies. This is thanks in part to inter-individual variations of neurocognitive function, but also because we know and understand that the human brain and nervous system can be stimulated or modulated with various electrical stimulation parameters, much like modern computing systems and medical devices. The complexity of how these systems are networked and organised is what we’re yet to fully (or partially) discover.

Since the description of Gall’s phrenology, the cartography of the brain and delineation of function would continue to be explored, described and reinvented over and again by historical figures such as Bouillaud, Rolando, Broca, Fritsch & Hitzig, Bartholow, Wernicke, Brodmann, Foerster and Penfield as well as many, many others. In the three centuries since Gall’s description of phrenology we are at the cusp of a new era of understanding neural function, championed by contemporary surgeon-scientists such as Ojemann, Berger, Bello and Duffau. None of it is definitively ‘localised’, perhaps with exception of primary motor and sensory regions — though there is still variability. Rather, it can be considered a hodotopy: a series of interconnected ‘meta-networks’ of neural connections in the brain, each responsible for various cognitive, motor and sensory faculties, and each with important implications for patients with tumours impacting these networks.

“The past 150 years have allowed us to accumulate mountains of facts on the functional cartography of the primate brain” describes Professor Marsel Mesulam, writing the foreword for Duffau’s Brain mapping: from neural basis of cognition to surgical applications. “The human cerebral cortex alone contains 40 billion neurons crowed into 3 square meters of surface area. Each neuron makes thousands of synaptic contacts through which information rapidly flows from one neuron to another. The total number of neural contacts on the surface of the brain is in order of 40 followed by 14 zeroes, a number that is as large as the number of all the stars in our galaxy”. This certainly gives the search for understanding of neurocognitive function gravitas, and also credence to Duffau’s two-decade journey thus far.

Born in 1966 in Montauban, France, Duffau recalls his initial interest in medicine. “When I was young, I was impressed by our general practitioner who was (passionate about) his work, and my goal was to become a family doctor to enjoy a unique relationship between medical doctor and patients.” Whilst he describes a fascination with the brain, he also shared a great enthusiasm towards music, “The first aim was to make people dream, so I wanted to be an artist, a musician.”

Having completed his medical residency in Paris, Duffau travelled to the U.S. for a fellowship program focused on functional neurosurgery with globally-renowned functional neurosurgeon Professor George Ojemann. ‘George Ojemann was a pioneer, he did not develop a ‘stimulation technique’ but an original philosophy’ with regards to awake brain tumour surgery, and one that has been continuously recognised as the turning point for awake neuro-oncological surgery involving eloquent areas of the brain. Many consider Professor Ojemann as the contemporary ‘forefather’ of functional neurosurgery, and rightfully so given that he has a widely used electrical stimulation device named after him.

In 1999, Duffau published his first single-centre experience with surgical brain mapping, claiming that it constituted ‘…a reliable, precise and safe method, allowing the realization of a functional mapping useful for all operations of lesions located in eloquent areas’. Some 420 papers exploring somatotopy, brain tumour surgery, and direct electrical stimulation mapping followed over the next two decades.

The challenge of surgery for brain tumours, describes Duffau, is respecting the ‘onco-functional balance’, that is, to remove cancerous tissue whilst preserving quality of life by not compromising neurological function. “This is the reason why the new generation should understand very early the connectomal account of neural processing in order to adapt their surgical strategy in the central nervous system accordingly, otherwise they will be ideologically (and not technically) limited all their life.”

Duffau recently published a seminal collection of data from neuro-imaging, lesional and psychiatric studies in Physiology Review, detailing a meta-networking of human cognitive function, including complex higher order function such as emotion, arithmetic and language. This he regards as a very important assemblage for the next generation of neuroscientists and neurosurgeons, and certainly a far-cry from the interpretation of conformations of the human skull. This also has important implications for his day to day surgical practice. “Recently, I mapped the networks involved in empathy in a psychiatrist because he told me before surgery, that he absolutely wanted to be able to continue to deal with his patients,” describes Duffau. “…so, you see that we are doing a kind of ‘mapping a-la-carte’ — designed for each patient individually — according to his/her quality of life — that they should define before surgery.”

Awake brain surgery is not a recent surgical intervention, though it is sometime featured as a novelty. When asked his opinion of the many television news stories of patients playing guitar or violin during awake surgery, ‘It is only to make a scoop. I have never asked to the musicians I have operated on to play music during surgery, and all of them have been able to resume their artistic life after resection. The real interest is to understand the neural foundations of such a creativity, by investigating the dynamic interactions between function-specific networks necessary to reach this level of integration, for example, the elaboration of a transitory meta-network (network of networks) allowing an adapted complex behaviour’.

In my own decade-long journey in clinical neuroscience, I had admired Duffau’s work in the same vain as his contemporaries. It was practical and complex, almost eponymous and patient-focused. I was fortunate to see him speak in person at neurosurgical conferences in New Orleans and then in London in 2018, and it quickly became apparent that his tenacity for understanding the human brain fuelled his very existence. He spoke with unbridled enthusiasm, although at a borderline-alarming pace. Having personally studied ‘traditionalist’ cognitive sciences, to hear a neurosurgeon encourage other surgeons to ‘…resect Broca’s area with impunity!’ was somewhat controversial seeing as though this region of the brain has long been associated with the ability to produce speech. Duffau maintains this sentiment. ‘Surgeons who do not want to accept that and who continue to believe in localizationism, cannot go through “Broca’s area” because they are still under the weight of rigid dogmas they have learned when they were residents.”

Based on his research, though, neural plasticity is best achieved only under certain circumstances; lower-grade lesions, younger patients, and with less preoperative infiltration, for example. It should also be partnered with extensive neuropsychological and physical rehabilitation. In an interview with Ku Leuven, Duffau notes that that with the help of a specific rehabilitation programme, patients scored better in cognitive tests three months after surgery than they did before surgery. “This is not science fiction. We are really capable of doing this. The postoperative possibilities of neurosurgery are just amazing, particularly if the patient is doing well before surgery.”

Duffau’s insistence that localizationist concepts of neurological surgery are redundant might ruffle the feathers of his peers, given that the treatment of brain cancer involves a multidisciplinary approach. Surgery is but one aspect of clinical treatment, though at present it represents the greatest chance of extending life in patients with gliomas. This is why Duffau believes every opportunity to map cognitive function needs to be explored, as it not only attempts to prevent debilitating neurologic injury, but might also provide meaningful insight as to how the brain is capable of experiencing ‘recovery’. “Plasticity exists in patients,” he notes, “but sometimes it’s very difficult to find plasticity in researchers and medical doctors”.

When I asked Duffau what kind of roadblocks he’s encountered on his journey, he quickly cites conservatism, dogmas, ‘weight of the history’, inertia and a fear to innovate. Similarly, when I ask him as to what kind of advice he can offer those interested in a career in neuroscience or neurosurgery, he provides a cacophony of inspirational instructions.

“Be innovative by creating unlikely links between different fields, have confidence in yourself, dare to propose new things based on a multimodal background, avoid to follow protocols, achieve each surgery as if your own life depended on it, as a piece of art, challenge dogmas, work hard to continue to learn and build original theories throughout your life, validate your results, avoid to become monothematic, remain passionate, never forget empathy and mentalizing, elaborate new individualized therapeutic strategies tailored to each patient: so, as a medical doctor and scientist, be first a human being, and make people live AND dream.”

When reflecting on the thousand-plus patients he’s treated from five continents and of various ages, languages, and cultures, it’s obvious he’s inspired by the resilience of the human condition. “I know that each human being has the capability of surpassing him or herself. Therefore, my substantive question, beyond neurosurgery and neurosciences, would be to understand why too frequently people wait to have a real problem in his/her life, like a brain tumour, for such a sublimation. My main message is that we can all transcend ourselves if we wish.” Though speaking metaphorically, transcendence is all-too appealing to someone like Elon Musk.

In 2017, having conquered online payment systems and championing the development and mainstream introduction of performance-focused electrical vehicles, Musk established brain-machine interface company Neuralink to ‘treat serious brain diseases in the short-term, with the eventual goal of human enhancement’ long-term, describing a ‘symbiosis with artificial intelligence’. Whilst he is proven visionary, he’s not a medical doctor. I often try to ask functional neurosurgeons what they think of these kinds of claims, and their response is often disrepute or cautiously optimistic. When I asked Duffau, he remained objective. ‘The future of our specialty is to build an actual restorative neurosurgery. But it will not be possible if we improve technology without improving our understanding of human brain processing’.

Today, Duffau is the head of neurosurgery at Montpellier University Hospital, and also director of the INSERM team dedicated to exploring the plasticity of the central nervous system, human stem cells and glial tumours. He is a member of editorial boards of journals such as Brain and Language, Neurosurgery, Neuro-oncology and an ad-hoc reviewer for the New England Journal of Medicine, Annals of Neurology, Lancet Oncology, Nature Medicine and more. In amongst the publication of four textbooks and hundreds of peer-reviewed articles, his focus remains on the treatment of brain cancer patients. When I ask him how he manages his time amidst the chaos of a bustling schedule, he is adamant that ‘It is not a “chaos”, but just a coherency, a lifestyle: it is self-evident”. I receive a similarly direct response when trying to determine his preferred choice of food or wine (‘my answer to all these questions is that I am — I try to be — eclectic: so, I cannot answer’).

I’ve always admired neurosurgeons, and not for the reasons most people would expect. There’s a humanity to these individuals that a lot of people could afford to learn from, or appreciate. Quite literally they live to help others, and often under very dire circumstances. Duffau was recently asked what his proudest moment is to date, having achieved a vast number of esteemed and honourable recognitions in the scientific and medical community, “each time I meet patients and their family telling me that they are happy, because they continue to enjoy a normal life 5, 10, 15 years following surgery”.

It is an acrimonious exchange, a tumour in the eloquent brain and the potential insight and information that electrical brain mapping might yield during its removal. It’s unmistakeable that brain tumour patients have inadvertently provided a circumstance permissible to the wider understanding of neurocognitive function, often at the expense of an unfair and unfortunate prognosis. As doctors, surgeons and scientists are slowly beginning to understand how the brain might be organised, and under which circumstances it is capable of reorganising itself, treatment paradigms in neuro-oncological surgery are evolving with the information gathered in its wake. Amongst the melancholy, it is also unmistakeable that his admiration of the family doctor all those years ago continues to inspire Duffau as he continues to explore the resilience of human brain, one network at a time.

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