• Revenge of the Nerds: Functional Neurosurgery, Past and Future

    Author: Nicholas M. Boulis, MD

    Each subspecialty of neurosurgery has its own cultural archetype. Spine surgeons are jocks, vascular surgeons are fighter pilots, and functional neurosurgeons are nerds. We always have been, and always will be. What nerds love most is knowing what others don’t. We love it for the sheer enlightenment in it. To many of us, deeper existential questions of identity ultimately spin back to neural function. And in the manipulation of neural function through physical intervention, we confront in its most manifest form that which we are. Functional neurosurgeons love the power in that idea, because viewed from the outside, deep science, that edge where reality meets science fiction, is indistinguishable from magic. In the end, we are more drawn to the power of creation and technology than to poise and virtuosity. Nerds dream of magic.

    So where did the magic start? To answer this question, one needs to tell the stories of the methodology and neurobiological understanding. The notion that the function of the human brain could be manipulated through specific anatomical alterations finds its roots in the emergence of localization. The idea that specific neuroanatomical locations could be correlated to individual elements of human behavior and experience is generally credited to the phrenologists. Franz Joseph Gall introduced the idea of “mental faculties” in 1796. In The Anatomy and Physiology of the Nervous System in General, and of the Brain in Particular, with Observations upon the possibility of ascertaining the several Intellectual and Moral Dispositions of Man and Animal, by the configuration of their Heads, published in 1819, Gall professed several key principles. First, the brain is the organ of mind. Second, the brain was a collection of anatomically distinct suborgans dedicated to specific functions. While these first principles led to a variety of erroneous conclusions, they also provided the phrenology head which adorns many of our offices and makes a great hat rack. They also influenced early neuroanatomists like Pierre Paul Broca, who published “Sur le principe des localisations c?r?brales” in the Bulletin de la Soci?t? d”Anthropologie in 1861. The observation the role of Broca’s Area in speech helped to prove Gall’s principles. Interestingly, Broca also concluded the larger size of the male brain proved the intellectual superiority of the sex. The importance of size remains a contentious issue for both genders.

    John Fulton captured in a particularly nerdish moment… because, let’s face it, functional neurosurgery is not just fun, it’s funny.

    In any case, proof that neural function could be dissected into specific anatomical regions evolved the notion that human experience and identity are fundamentally created by neuroanatomical structures subserving electrochemical events, i.e., The Matrix. Nerds love The Matrix, the veracity of which is generally accepted by the Illuminati of the Functional and Stereotactic Section. It wasn’t long until the fairly cool concept of cerebral localization found application in surgery. In 1890, the Swiss psychiatrist Gottlieb Burckhardt attempted cortical resections to address various psychiatric symptoms with only a 16.5 percent mortality rate. In the 1930s, notable Yale-Harvard nerd, John Fulton, conducted a series of chimpanzee experiments demonstrating that lesions of the prefrontal cortex could lessen anxiety effects. This work inspired Egaz Moniz to propose the prefrontal leucotomy in 1935. Moniz went on to win the Nobel Prize for this work in functional neurosurgery, an improvement over his earlier cerebrovascular work, for which he was only nominated for the Nobel. (It is believed that this early “failure,” along with extreme nerd tendencies, led to his career shift.) However, it was Walter Jackson Freeman who had the messianic mission to make transorbital frontal lobotomies accessible across the country. The over-application of the technique, poor external ethical control, and the imprecise nature of the procedure created a backlash from which functional neurosurgery is still recovering.

    Concurrently, the movement disorder surgeons were exploring the resection of a variety of targets in the pyramidal system, including the cortex and corticospinal tract. While these approaches reduced tremor, they often created weakness. In 1927, Hugo Spatz proposed a role for extrapyramidal (basal ganglion) systems in motor control. This led to the first lesions of the extrapyramidal system by Russell Meyers in the 1940s. These operations largely centered on resection of the caudate head through a transventricular approach, with 62 percent positive results and a 14 percent mortality. At approximately the same time, Irving S. Cooper inadvertently cured tremor through an anterior choroidal artery occlusion that caused a stroke in the globus pallidus. Cooper and colleagues continued to innovate new ways to perform precise lesions. In 1953, Hirotaro Narabayashi pioneered stereotactic pallidotomy. Despite these advances, in the absence of CT or MRI, accuracy was limited. The introduction of L-Dopa in the 1960s dramatically reduced the need for movement disorder surgery, which fell into disuse for several decades.

    Egaz Moniz, MD (See what I mean?)

    Throughout the 1970s and ’80s, improved imaging and better stereotactic tools allowed functional neurosurgeons to revisit stereotactic lesioning. A better understanding of the circuitry of the basal ganglia, enumerated by Mahlon Delong, and created by the availability of the MPTP NHP model, added precision to our understanding of how these targets worked. And so the two stories continue, a progressive advance in our understanding of the underlying functional neuroanatomy, and ever-improving tools leading to reproducible, safe procedures.

    Nonetheless, all of these circuit manipulations depended on lesioning, a crude and irreversible technique. It was the Jedi Benabid who developed the use of adjustable chronically implantable electrodes that provided essentially the same effects as lesions with the benefit of not further damaging the nervous system, and allowed for removal and adjustment. The added safety provided by this new tool created a liberal environment for testing the efficacy of stimulation in a wide range of targets, ushering in a sort of Wild West environment for exploration, some with limited conceptual basis, and others with extremely well-reasoned targeting. One example is the work of Helen Mayberg, which identified a target in the subgenual cingulate that she predicted to correct depression states. While the primary RCT failed for this, we continue to see refinements in targeting that promise future success.

    Just as there have been an explosion in putative targets for the alteration of functional neural states, so too have the potential tools for intervention expanded. On the engineering side, interventional MRI approaches emerged for DBS implantation, eliminating the need for awake surgery. In addition, a number of tools have emerged for precise lesioning, including implanted lasers and focused ultrasound. Most impressive is the emergence of the concept of the brain-computer interface (BCI), which leverages a human’s innate capacity to adjust the activity of fields of cortical neurons as new motor tasks are learned. By implanting an array of electrodes either into the cortex or the epidural space, a human can learn to create specific patterns of activity that can be recognized to encode vectors, thereby allowing for the control of computers and robots. We look forward to a future where devices with control implanted efferent electrodes that stimulate movement in the body will restore the ability to stand or walk. To date, the biggest barrier to BCI has been maintaining stable arrays of recordings over time.

    Finally, new techniques have emerged that will allow for a new level of control of neural targets. Lesions and electrical stimulation are fundamentally nonspecific approaches, affecting white matter and gray matter alike. Moreover, they affect all neuronal types in the region of stimulation. The emergence of optogenetics and chemogenetics will provide this new level of specificity. In the case of optogenetics, the genes encoding photoreceptor membrane proteins (channel rhodopsins) are delivered to neurons in a specific target. Because expression is controlled by cell-specific promoters, only particular cells will bear the photoreceptor. These cells can be activated by specific wavelengths of light, allowing for differential control of neuronal subpopulations in a given target by expressing different channel rhodopsins under the control of different promoters. If DBS was a snare drum, optogenetics is a symphony. Unfortunately, control still depends on an implanted light source, with many of the disadvantages of implanted DBS, including infection and device failure.

    Chemogenetics, like optogenetics, uses the delivery of the gene for a mutant receptor. These receptors are sensitive to novel ligands. As such, one can activate the neuronal subpopulations expressing the channel/receptors with the administration of a drug. In this scenario, patients will require no implanted device while still achieving a whole new level of control and specificity.

    So, while what’s going on behind the closed doors of functional neurosurgery may not be everyone’s cup of tea, look forward to some quantum leaps in tools and understanding. It’s been a great ride so far.

    < Many of the historical facts discussed in the present piece were taken from a lecture originally prepared by Brian Kopell, MD, who hides his nerd tendencies well, but is, nonetheless, pretty square.

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