Progress in brain research, volume 215

Advisory Editors Stephen G Waxman Bridget Marie Flaherty Professor of Neurology Neurobiology, and Pharmacology; Director, Center for Neuroscience & Regeneration/Neurorehabilitation Research Yale University School of Medicine New Haven, Connecticut USA Donald G Stein Asa G Candler Professor Department of Emergency Medicine Emory University Atlanta, Georgia USA Dick F Swaab Professor of Neurobiology Medical Faculty, University of Amsterdam; Leader Research team Neuropsychiatric Disorders Netherlands Institute for Neuroscience Amsterdam The Netherlands Howard L Fields Professor of Neurology Endowed Chair in Pharmacology of Addiction Director, Wheeler Center for the Neurobiology of Addiction University of California San Francisco, California USA Elsevier Radarweg 29, PO Box 211, 1000 AE Amsterdam, Netherlands The Boulevard, Langford Lane, Kidlington, Oxford OX5 1GB, UK 225 Wyman Street, Waltham, MA 02451, USA First edition 2014 Copyright # 2014 Elsevier B.V All rights reserved No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein) Notices Knowledge and best practice in this field are constantly changing As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein ISBN: 978-0-444-63520-4 ISSN: 0079-6123 For information on all Elsevier publications visit our website at store.elsevier.com Preface No invention or discovery is ever produced in a vacuum First, there must be a perceived unfulfilled need This will usually be followed by attempts to satisfy that need which may not always be successful The most familiar example of persistent lack of success is the alchemists’ failure to transmute base metals into gold One of the sequences of this kind applied to medicine is the introduction of a new treatment concept From concept to fruition in the form of a usable new method is painstaking and time consuming This part of the process may involve useful but suboptimal new ideas or methods which require repeated adaptation Chance also plays a part Moreover, a treatment perceived imperfectly initially may be improved by totally different persons from those who first initiated the new notions and the honor may well go to the discoverer of the successful adapted method rather than to the original creative thinker who initiated the investigations which ended in success Furthermore, along the way, a conservative profession, concerned for both the patients under its care and the standard of living of its members, may well oppose anything new because unproven novelty may threaten both patients’ safety and practitioners’ domestic luxury This sequence of partial success, acceptance, and resistance to change and final success of a truly effective new method should be seen as characteristic of medical advances which, like it or not, are sought and implemented by human beings with all our talents, virtues, and weaknesses No better example of the sequences involved can be found than the series of events which led to the discovery of smallpox vaccination Lady Mary Wortley Montagu (1689–1762), daughter of the Earl of Kingston upon Hull, was a woman of beauty, wit, and independence of spirit unusual at her time Her father pressed her to marry a man of distinction and property with the positively Dickensian cognomen of Clotworthy Skeffington, an Irish nobleman whom she did not fancy So she eloped in 1712 and married Edward Wortley Montagu in Salisbury In 1715, she contracted smallpox which she survived but with some scarring Her brother died from the disease She had previously been a Court favorite but her satirical writings about the Princess of Wales, written while she was sick barred her from Court She thus joined her husband who had been appointed British ambassador to Turkey There she encountered the practice of variolation whereby matter from an infected person was injected into the vein of someone to induce a mild attack of the disease, hopefully with minimal scarring and lifelong immunity The procedure was not without risk because some inoculated individuals could suffer a severe form of smallpox which could prove lethal Nonetheless, its acceptance by the upper reaches of society led to its increasing use One of those who had survived variolation but was never as fit afterward as he had been before was Edward Jenner (1749–1823) While trained by the best in London, he was at heart a country boy and returned to practice in Berkeley in Gloucestershire where his museum is found to this day As a country doctor, he had heard of the practice of inoculating milkmaids with a bovine form of the disease conferring immunity Due to the rarity of cowpox, v vi Preface it was not easy to perform routine inoculations, but those who were inoculated never suffered smallpox, including Jenner’s little son The success of the procedure needs no further comment Nonetheless, the method was criticized in the medical profession, not least by those who received substantial fees for performing variolation so that it was a time before the treatment became universally accepted This sort of reaction following the introduction of a new method in surgery is not unfamiliar One could consider Semmelweis and hand washing and Lister and antisepsis, neither of whom received rapturous applause for their contributions During the passage of this book, it will be seen that the processes which ended up with the discovery of smallpox vaccination would also affect the invention of radiosurgery and the perfection of instruments for its satisfactory performance This will be particularly illustrated in Chapter 11 In the 1930s, the treatments of inaccessible cancers and neurosurgical diseases were frustrating and inefficient However, this was a time when understanding of atomic structure and spontaneous breakdown of unstable radionuclides was expanding rapidly The frustration with the poor results of existing treatments was the spur to develop new methods The first to attempt the use of atomic particles in radiation treatments were the Lawrence brothers in Berkeley, California, spurred on by no less a person than Harvey Cushing, who contributed to John Lawrence’s training and clearly had a great respect for him The elder brother Ernest invented the cyclotron to accelerate subatomic particles The younger brother, John Lawrence, pioneered the use of these particles in the treatment of disease using both radioactive nuclides and later well-defined narrow particle beams It should however be mentioned that the Berkeley group, while performing extraordinary creative work, were applying a medical function to a machine designed for a different purpose In Sweden, a group of scientists developed and expanded the Berkeley technique to the point where the clinical treatment of a variety of conditions became possible The Swedish group were in contact with the Berkeley group and express their indebtedness in a number of their papers However, while the particle beam method was elegant, it was also complex and impractical outside of a laboratory containing a cyclotron which could generate the particles This led to the design and production of the only machine in the world which was specifically constructed to perform radiosurgery, the gamma unit subsequently to be called the Gamma Knife The purpose of this book is to trace the history of the ideas and attempts at radiosurgery treatments from the first hesitant steps in California to the production of the most modern radiosurgery machine the Gamma Knife Perfexion The part played by chance is well illustrated in the above account of vaccination Mary Montague was a girl of spirit who opposed her father, married the man of her choice, sustained smallpox, wrote the wrong thing, and had to travel to Turkey where she came into contact with variolation which she was in a social position to introduce into London society Jenner was a country lad at heart but during his time in London suffered uncomfortable effects following variolation and was as a country doctor in a position to be aware of cowpox and the smallpox resistance of milkmaids The Lawrences were both talented but by chance John came into contact with Harvey Preface Cushing who supported the activities of him and his brother and World War II inevitably did no harm to funding the laboratory where the work was carried out In Sweden, Leksell started a medical career by chance and was possessed of a mindset which enabled him to design useful instruments, perhaps in part because as a child he’d had the chance to work under supervision in the machine shop of the factory his father owned He also had access to a supremely talented physicist B€orje Larsson 20 years his junior without whom the gamma unit would not have been possible One consequence of Leksell’s social position was his net of personal relationships, which included Bo Ax:son Johnson one of the owners and directors of the wealthy Axel Johnson Group which during the relevant period owned the Studsvik nuclear power plant, the Motala Verkstad engineering workshop, and the Avesta Jernverk a workshop which also specialized in metal work The Johnson Group thus owned all the industrial facilities which would be required to manufacture a radiosurgery machine While there remains evidence of a detailed and comprehensive interest on the part of the Swedish state to ensure the new machine’s specifications and patient safety were acceptable, there was no financial assistance from the state The contribution from national coffers was limited to grants for the research work in Uppsala during the 1950s and 1960s which would form the basis for proceeding with a commercially produced machine Thus, Leksell’s relationship with senior levels of the Axel Johnson concern was a happy chance for the development of the original gamma unit, leading to the entirely private financing of the machine’s development and manufacture arising out of respect Bo Ax:son Johnson had for Leksell’s work In conclusion, it should be remembered that the nature of scientific advance means that a day will come when the Gamma Knife Perfexion is not the best instrument for its purpose However, that day has not come yet and there is no sign that it will come soon vii Acknowledgments The author would like to thank the following people without whose invaluable advice and assistance this book could not have been written First, Dr Dan Leksell, the son of the inventor of the Gamma Knife, has been free with information about the early days of radiosurgery and has given access to relevant papers which would otherwise have been inaccessible He has also been an invaluable adviser on textual purity Next, there is Dr Bert Sarby a physicist who was intimately involved in the development of the early gamma unit and has given freely of his time and his literature to ensure the accuracy of the text Hans Sundquist, the engineer who turned the ideas of designers into practical machines, has also listened to the author’s questions and answered promptly and concisely whenever approached I should like also to extend my gratitude to Dr Rich Levy from Berkeley who was generous with his time and information about cyclotron radiosurgery Finally, to my old friend Juărgen Arndt another physicist with whom I have roamed the world teaching the practice of radiosurgery from Mexico to Tokyo via Beijing He has repeatedly advised on the evolving text All of the above persons have not only advised on this project but also have read through the text to ensure their information is correctly relayed It would be remiss of me if I did not also thank Professor Erik Olof Backlund, my chief in Bergen and my mentor in the mysteries of radiosurgery He has been a kind and consistently enthusiastic support over the years and has also been helpful in supplying valuable and otherwise unavailable details from the early days Finally, I should like to thank my wife, Gao Nan Ping or Annie Gao, as she is known to her many friends in the radiosurgery milieu The wife of any man writing a book has to put up with the absences, trips, and changing moods of the author as he pursues his aims Without Annie this book could not have been written xv CHAPTER Background knowledge in the early days Abstract The purpose of this chapter is to outline the medical facilities that were available to the inventors of radiosurgery at the time when the technique was being developed This is achieved by describing in brief the timeline of discoveries relevant to clinical neurology and the investigation of neurological diseases This provides a background understanding for the limitations inherent in the early days when investigations and imaging in particular were fairly primitive It also helps to explain the choices that were made by the pioneers in those early days The limitations of operative procedures and institutions designed to treat neurological diseases are also mentioned Keywords clinical neurology, radiology, contrast studies, operating theaters, neurological hospitals INTRODUCTION Radiosurgery was first defined by Lars Leksell in the following terms: “Stereotactic radiosurgery is a technique for the non-invasive destruction of intracranial tissues or lesions that may be inaccessible to or unsuitable for open surgery” (Leksell, 1983) As stated in this section, no human activity occurs in a vacuum including the development of medical technology Radiosurgery was developed out of the perceptions and efforts of a small group of men who passionately believed that such a method was urgently needed in the battle against a large number of contemporaneously untreatable diseases The possibility of developing radiosurgery was a spin-off of the developing field of nuclear physics, which was such a characteristic development of the first half of the twentieth century What was required would not be clear at the start, but would become so There were five essential elements The first chapters of this book concern the journey toward understanding and eventually the implementation of these elements; and it was a long journey: Progress in Brain Research, Volume 215, ISSN 0079-6123, http://dx.doi.org/10.1016/B978-0-444-63520-4.00001-6 © 2014 Elsevier B.V All rights reserved CHAPTER Background knowledge in the early days Images that enable the visualization of the lesion to be treated are an essential part of the method A three-dimensional reference system common for imaging, treatment planning, and treatment A treatment planning system by means of which the irradiation of each case can be optimized A means of producing well-defined narrow beams of radiation that selectively and safely deliver the radiation dose under clinical conditions Adequate radiation protection CLINICAL NEUROLOGY This book concerns neurosurgery and neuroradiosurgery and surgery of the central nervous system (CNS) At the time when the processes that would lead to neuroradiosurgery were beginning—around 1930—neurosurgery’s contribution to patient welfare, while more rational and scientifically based than any at the time in its previous history, had relatively little to offer Certainly, cell theory had permitted the analysis of the cellular components of the CNS and their architecture and interrelationships Based on this new knowledge, clinical neurology had made great strides with the development of the examination of the CNS based on the understanding of how its different components were interconnected (Compston, 2009) John Madison Taylor had introduced the reflex hammer in 1888 (Lanska, 1989) Gradual understanding of how to examine the CNS was propounded by Joseph Babinski (1857–1932) in 1896 (Koehler, 2007) Ernst Weber (1795–1878) and Heinrich Adolf Rinne (1819–1868) had introduced means of distinguishing between conductive and neurogenic hearing loss although the precise date of their tests has proved impossible to determine These tests require tuning forks that had been originally invented by John Shure (ca 1662–1752) reaching the advanced age for the time of 90 years He was distinguished enough that parts were written for him by both Haăndel and Purcell (Shaw, 2004) It was applied to neurological testing first in 1903 (Freeman and Okun, 2002) The ophthalmoscope was invented by Helmholtz in 1851 (Pearce, 2009) It was developed and its source of illumination was improved over succeeding decades During my time at the National Hospital for Nervous Diseases, Queen Square, London, I was told that such was the value given to ophthalmoscopy that there was a time when junior doctors at Queen Square were required to examine the fundus of patients suspected of raised intracranial pressure (ICP) every 15 In 1841, Friedrich Hofmann invented the otoscope (Feldmann, 1995, 1997) In the 1930s, the examination of the CNS was becoming fairly precise and this precision would improve over the decades to come until the arrival of computerized imaging in the 1970s and 1980s Until then, clinical examination was the most accurate method for localizing pathological processes However, not all clinical symptoms arise from identifiable foci of diseases Thus, subacute combined degeneration of the cord gives a complex picture with some tracts affected more than others Investigations Again, in multiple sclerosis, with intermittent lesions varying in time and space, a simple localization from clinical information would be difficult However, this is not that important for the performance of a surgical technique of which radiosurgery is one because surgical conditions are single and focal in the vast majority of cases The advances described in the previous paragraphs greatly increased the accuracy with which a skillful clinician could localize the position of a pathological process within the CNS Even so, the first systematic monograph on clinical neurological localization was published as late as 1921 by a Norwegian, Georg Herman Monrad-Krohn (1884–1964), writing in English (Monrad-Krohn, 1954) In 1945, the more or less definitive text by Sir Gordon Holmes (1876–1975) was published (McDonald, 2007) INVESTIGATIONS 3.1 ELECTRICAL As far as functional investigations were concerned, electroencephalogram (EEG) became commercial in 1935 and electromyography (EMG) arrived in 1950 3.2 IMAGING In terms of further radiological investigations, the first visualization of the CNS came with the use of contrast-enhanced X-ray studies introduced by Cushing’s student Walter Dandy (1886–1946), specifically pneumoencephalography (1918) (Dandy, 1918) and pneumocisternography (1919) (Dandy, 1919) While these examinations were undoubtedly an improvement, yet to modern eyes, they still look primitive Then, in 1927, came carotid angiography that while a further improvement was still limited and not without risk Vertebral angiography became routine in the early 1950s A brief description of the way these methods works follows Since the first radiosurgery information was published in the early 1950s, it is necessary to see how the necessary imaging for radiosurgery could be achieved at that time If we bear in mind that the technique was solely used for intracranial targets, there were basically three imaging techniques 3.2.1 Plain Skull X-Rays Plain skull X-rays existed but were of little value in showing targets suitable for radiosurgery The right side of Fig shows an X-ray of the skull, taken from the side, and indicates that the only reliable location of an intracranial soft tissue is the position of the pituitary gland (see Figure 4) Following 1918, it became clear that parts of the brain could be demonstrated using what are called contrast media These are fluid substances (liquid or gas) that affect the passage of X-rays through the skull Either they let the rays pass more easily, in which case they will darken the part of the image where they are, or they will stop them passing so easily, in which case the portion of the image-containing CHAPTER Background knowledge in the early days medium will appear lighter The most frequently used medium in this context was air and how it worked requires some explanation 3.2.2 Brain and CSF Anatomy It is necessary to digress a little and explain some facts about intracranial anatomy The brain sits tightly enclosed within the skull but it is floating in a bath of fluid called cerebrospinal fluid (CSF) This is created at roughly 0.32 ml/min Figure is a diagram of the anatomy of the brain and the fluid-filled spaces (called ventricles) that it contains Figure illustrates how the CSF is made in the ventricles and flows through the brain It leaves the ventricles and flows over the brain between two membranes, the pia mater and the arachnoid The pia mater means soft mother and is called that because it embraces the brain as a mother embraces her child The arachnoid is so called after some imaginative anatomists looking through the microscope considered that the membrane and the space under it looked like a spider’s web In Greek mythology, a skillful but arrogant young lady called Arachne challenged Athena, the goddess of among other things weaving, to a weaving contest The girl inevitably lost and was turned into the world’s first spider Thus, spiders are called arachnids and this explains the use of the term arachnoid in the current context It should be remembered that at any one time, there is about 150 ml of CSF in the system and two-thirds of it is outside the brain in the subarachnoid space 3.2.3 Contrast Studies: CSF Replacement Studies Let us return to imaging Plane X-rays were of little help, but in 1918, Cushing’s pupil Walter Dandy had discovered that the introduction of air to replace the CSF could provide demonstration of the ventricles of the brain and any distortions or displacements of that system The air could be introduced either into the spinal canal FIGURE This diagram illustrates the shape of the ventricles within the brain There are two lateral ventricles to the side of the midline in each cerebral hemisphere, and the third and fourth ventricles in the midline are connected by the aqueduct Introducing the APS: the C model Thus, while the reader may refer to Chapter to see the shape of the machine and the way the patient would have to be lifted into position, in Fig 6, it is possible to see how much simpler the model B was INTRODUCING THE APS: THE C MODEL These constant delays due to exchanges of collimator helmets were not in keeping with the elegance of the treatment method, and a solution was found that came into use in 1999 With this system, it was no longer necessary to change the patient’s position with a specific helmet The system, called the automatic positioning system (APS), replaced the adapters, bars, and trunnions of the earlier model However, there is one note to be made The original model used in the United States, the so-called U model, was gradually replaced after the American authorities licensed the B model that had been in use in all other countries It was this model that was the basis for adaptation to the APS system While the U model was U for USA and the B model was B for Bergen, the C model was C that follows B The APS system is shown in Fig This system had two advantages Because it was no longer necessary to change the patient’s position manually between each shot, dose plans with more, smaller shots and better conformity could be designed It was also marginally more accurate than the trunnions However, there were two problems it did not solve The first was the need to change helmets, which still had to be done manually The second was the matter of plugging (Fig 8) FIGURE The three black arrows (going from right to left) point to the elements of the APS, which move the patient’s head up and down (Z-axis), backward and forward (Y-axis), and from side to side (X-axis) The author is grateful to Springer Verlag for permission to use this image 121 122 CHAPTER 13 Changing the gamma knife FIGURE A dose plan with five of the six shots shown The shape of the radiation from any shot can be changed by plugging some of the collimators Up to 100 collimators may be plugged FIGURE The diagram shows a possible plugging pattern PLUGGING The basic elements of dose planning with the Gamma Knife consist of placing shots of different sizes to create a plan that matches the margins of a target and avoids sensitive local structures at risk This is shown in Fig In Fig 9, a possible pattern of plugging is shown Since each collimator has to be replaced manually with a plug, it is easy to see that this is a tedious and time-consuming activity The avoidance of plugging was introduced with the most recent Gamma Knife the “Perfexion.” It may not have been a major reason for the redesign of the machine, but its absence is surely much appreciated by all whoever had to replace multiple collimators with plugs Perfexion PERFEXION With technology, the urge to improve is and should be a constant feature The direction improvements take will in at least some measure follow the needs of the users A major change occurred in Gamma Knife practice at the end of the 1990s and the beginning of the twenty-first century Cerebral metastases became an increasingly important indication because of the huge number of these patients Even with the 33 cm opening in the helmets of the Gamma Knives then in use, metastases posed a special problem They were multiple and could be anywhere, so that even the most skilful frame placement might not permit access to all the lesions in a single session Thus, it became increasingly clear that more room was needed inside the Gamma Knife collimator helmets Another feature was that metastasis patients requiring complex dose plans may also be very sick or in pain requiring a speedy treatment The consequence of all these requirements was the Gamma Knife Perfexion There was more space Plugging could be controlled by software with internal plugging available within the machine Collimator sizes could be changed internally without the need for the manual changing of helmets In other words, once a dose plan was finalized, the patient could be treated without further intervention by the treating team Press the button and wait until the procedure is complete FIGURE 10 This shows the different dimensions inside previous models of the Gamma Knife on the left and within the tungsten cone section on the right Our experience is that patients who are impossible to treat for a variety of reasons (extreme eccentric location +/À craniotomy) with the earlier models of the Gamma Knife can easily be treated with Perfexion The holes in the tungsten conic section lie over the deeper collimators, which penetrate all the way through the metal but which cannot be seen in this image The author is grateful to Springer Verlag for permission to use the image on which this figure is based 123 124 CHAPTER 13 Changing the gamma knife Perfexion is not a modification of any existing Gamma Knife It is a new design whereby the irradiation reaching the patient may have characteristics similar to earlier models However, the new design permits more space, better patient comfort, and faster treatments, since there are no helmets to change It also in principle would allow the treatment of cervical lesions, though this possibility is not practically available at the time of writing 6.1 DESIGN DIFFERENCES There is no helmet Treatment occurs inside a hollow tungsten mass through which 192 collimator channels have been drilled The difference in the available space is shown in Fig 10 The sources are not mounted in a fixed position in an outer helmet Instead, they are mounted on eight movable sectors Each of these sectors contains mm mm 16 mm FIGURE 11 This shows a diagrammatic longitudinal section through the Gamma Knife Perfexion The author is grateful to Springer Verlag for permission to use the image on which this figure is based (1) The black straight lines are the gamma rays meeting at a focal point (2) They pass through white tubes that are the collimators drilled through the tungsten conic section (3) The double-headed long white arrow indicates the tungsten conic section (4) The doubleheaded black arrows indicate the sources embedded in the sectors (5) The single-ended white arrows indicate the sectors (6) The white arrowheads indicate the motorized rods, which may slide the sectors along the surface of the tungsten conic section so that sources are either over a collimator or not (7) There are eight such sectors surrounding the conic section, and each sector can be selected to irradiate through any one of the three available collimators or to take an intermediate position and thus be blocked (8) The position on the left with the front collimators is 16 mm, the intermediate is mm, and the posterior is mm (9) The blocked position between collimator locations is not shown (10) The sectors may be withdrawn away from the collimators altogether to a resting position, which is also not shown Perfexion 16 mm collimator sector position at the front 16 mm beams mm beams mm collimator sector position further back NB each sector has 24 openings FIGURE 12 Note the 3-D appearance of two of the eight sectors It can be seen that each sector contains 24 openings The 16 mm collimator sector is at the front, and appropriately, the mm collimator sector is further back The beams from both can be seen to cross at the center of the system as described The author is grateful to Springer Verlag for permission to use the image on which this figure is based 24 sources given a total of 192 The arrangement is illustrated in the diagrams in Fig 11 The eight sectors surround the head The holes in the tungsten cone section, which sit over the collimators, can be seen in Fig 12 There are only three collimator sizes—4, 8, and 16 mm In view of the very different geometry of this system compared with previous Gamma Knife models, the system was extensively tested before being taken into commercial use It unquestionably makes the use of the Gamma Knife speedier and more efficient for the user while permitting access to any location within the cranium and making the process more comfortable for the patient 125 CHAPTER Conclusion and possible future trends 14 Abstract No technology will continue unchanged indefinitely The Gamma Knife Perfexion sets a gold standard today, but at some unspecified future date, new ideas will emerge, though none seem to be likely in the short term The treatment of neurosurgical conditions today cannot be sensibly undertaken by single practitioners Teams, consisting of members with the appropriate expertise, are required to meet and discuss and agree on patient treatment that is then allocated to one or other members of the group Conflicts will always arise but their effects can be minimized by the use of treatment teams and awareness of past conflicts and their speedy discharge into wastebasket of medical amnesia Keywords future developments, disagreements, Lars Leksell FINAL THOUGHTS Gamma Knife radiosurgery was introduced at the end of the 1960s to treat functional disorders of the brain and is used now, for the most part, to treat tumors and vascular malformations It was initially designed to treat very small volumes It is unlikely that it will be able to treat really large targets but it is also possible that it may be safely used with targets that are somewhat larger than those currently accepted as appropriate This brief history has illustrated a number of factors that affect the introduction of something new The medical milieu is innately conservative, which is understandable and often beneficial but not always and not inevitably so This conservatism is encapsulated in Claude Bernard’s remark, “L’homme et naturellement me´taphysicien et orgueilleux” (Man is by nature metaphysical and proud) But men such as Leksell seek to battle against this conservatism to make for a better world As Robert Browning stated in Andreas del Sarto, “Ah, but a man’s reach must exceed his grasp or what’s a heaven for?” Progress in Brain Research, Volume 215, ISSN 0079-6123, http://dx.doi.org/10.1016/B978-0-444-63520-4.00014-4 © 2014 Elsevier B.V All rights reserved 127 128 CHAPTER 14 Conclusion and possible future trends It is also not unfair to mention that Leksell’s conservatism as he grew older doubted the possibilities of spreading the Gamma Knife technology to more than a few centers and it would be the task of his sons and colleagues to show that in this, his judgment was fallible Indeed, the Gamma Knife has been an enormous success with over 300 Gamma Knife centers in the world, and of these, already over half are using the Perfexion machine Many people have contributed to that success Specific individuals have been vital to the success including Ladislau Steiner whose work on AVMs remains a standard and whose move to the United States helped to spread the word David Forster and Hernan Bunge also contributed to the international reputation of the method And of course, Dade Lunsford and his colleagues were essential for gaining a foothold for Gamma Knife surgery in the United States and subsequently to the rest of the world Moreover, the Pittsburgh group publications which were systematic, lucid, and honest greatly facilitated the spread of knowledge and the acceptance of the method Apart from physicians, many persons have contributed to the success but two seem to stand out as having provided a unique contribution Laurent Leksell’s ability to convince investors to back the Elekta company and his judgment in designing the structure of the company and its business methods must be accepted as key to its success Dan Leksell has facilitated the spread of Gamma Knife surgery in a variety of ways Helped by being medically qualified and having a very wide network of contacts in and outside the profession, he has contributed greatly to the spread of Gamma Knife knowledge, not least by his responsibility for the Leksell Gamma Knife society, whose meetings involving 500 participants every years are a huge ongoing undertaking Finally, every time I asked a question concerning the design about the construction of the machine, all the informed parties referred me to one person, Hans Sundqvist with his uncanny ability to turn concept and design into practical equipment QUO VADIS? Efforts to improve the mechanical and imaging accuracy of radiosurgery are ongoing, as they should be However, there is little likelihood that there will be dramatic improvements in these parameters in the foreseeable future Indeed, it seems unlikely that any such improvement could have anything but a marginal effect on the quality of treatment There is however an area of knowledge that would benefit greatly from investment in research This is individual radiosensitivity This is not an area related to radiosurgery per se but to radiation biology in general Anyone who has worked with therapeutic radiation will become aware that different people have different sensitivities to the same radiation dose What is needed is a simple clinical test that could be applied prior to treatment This would in time enable more sophisticated tailoring of the radiation dose to the particular patient’s requirements However, to date, this matter, because of its complexity and technical difficulty in practice, has received relatively little attention It is believed that a simple test as outlined above could Principles materially improve the quality of any radiation treatment It is believed that given time, such a test will become available Let us hope it is sooner rather than later PRINCIPLES The principles of Gamma Knife treatment are basically simple However, for them to be carried out optimally, the use of the Gamma Knife must be distributed between the members of a team No individual physician can possess all the necessary knowledge and experience to take single-handed responsibility for the treatment of the conditions described in this book 3.1 THE THERAPEUTIC TEAM This should be the basic unit involved in the treatment of the conditions under consideration Members of such a team should include experts from a mixture of specialties who refer and those who treat the patients and those who follow up the patients after treatment Team members with treatment expertise would have to include the following: Neurosurgeons Neuroradiologists Medical physicists Oncologists Nurses Team members who refer and follow up might include the following: Neurosurgeons Oncologists Neurologists Ophthalmologists Otolaryngologists Endocrinologists Every management team must have a chairman or leader and it seems logical that this task should fall to the neurosurgeon The diseases to be treated fall within his/her area of expertise Only the neurosurgeon can offer all three therapeutic options, surgery, radiosurgery, and wait and see Moreover, he/she is the only member of the treatment team with adequate experience in the clinical assessment of the neurological symptoms and signs and the effects of treatment on them In this, he/she is guided by the other members of the team The radiologist is vital to ensure the use of optimal technique for visualization of the target The oncologist is needed for the purpose of advising on radiobiology, dose and volume limitations, and, in the case of malignant tumors such as metastases, the integration of Gamma Knife Neurosurgery (GKNS) into a total treatment program directed for the benefit of the patient as a whole The 129 130 CHAPTER 14 Conclusion and possible future trends physicist is responsible for the technical working of the Gamma Knife, the accuracy of its dose planning, and the accuracy of the images imported into the dose planning system The value of the nurses needs no special explanation since no hospital treatment can work effectively without their participation and particularly their humanity 3.2 FUNCTIONS OF THE TEAM The initial function is to assess referred patients The reaction to a referral will lead to either acceptance for treatment, refusal, or a request for further additional treatment or investigation before a decision can be reached However, once the team has accepted a patient for treatment, it is to be hoped that every patient’s lesion will be planned where necessary for multimodality treatment from the start This would replace the current practice where the microsurgeon does his/her best and radiosurgery is required when safe radical surgery has not been feasible With multidiscipline planning, the surgeon could with modern stealth technology remove what is safe and accessible and leave the rest for GKNS The patient would be informed that this approach provided the optimal benefit in terms of disease control and safety from complications It cannot be emphasized too much that microsurgery and radiosurgery are not competing techniques but complimentary methodologies each fulfilling the other AVOIDANCE OF CONTROVERSY Some controversy will always be unavoidable as persons with differing qualifications and expertise involved in treating the same disease will approach the management differently The formation of therapeutic teams would go some way to reducing this kind of controversy Controversies are rooted in conservatism, threat of loss of income, ignorance, and intrusive journalism They can be reduced by openmindedness and goodwill but they are unlikely to disappear altogether The text of this book illustrates how the emotional bitter conflict of today all too easily is forgotten as irrelevant in a relatively short time CONCLUDING REMARKS The Gamma Knife is uniquely a machine designed specifically to perform cerebral radiosurgery It has been in use now for 45 years with astonishingly good results There are 313 machines spread across all the continents The method is simple to perform and it is easy to practice consistently between different centers The method is remarkably safe It is also an unusual treatment as it was evolved by clinicians and not engineers The sophistication of the modern Perfexion machine is a world away from the relatively clumsy yet effective early machines Moreover, any radiosurgery performed anywhere in the world on any part of the body, with any technology, would not have been possible without the insight, creative talent, and vast enthusiasm of the inventor of the Gamma Knife, Lars Leksell Index Note: Page numbers followed by f indicate figures and t indicate tables A Amber, 14–15 Aneurysm, 93 Angiography, 8, 8f Arteriovenous malformations (AVMs), 9, 9f, 93, 104–105 Artificial radiation, 31 Atom, 17 Automatic positioning system (APS), 121 AVMs See Arteriovenous malformations (AVMs) Axel Johnson Group, 71–72 B Battery, 15 Berkeley cyclotron, 27–28 Beryllium, 19–20 Blood vessels angiography, 8, 8f arteriovenous malformation, 9, 9f distortion/displacement of, 8, 8f meningioma, 8, 8f microsurgery, B model, 117–118, 118f, 119f Bragg peak, 33, 38, 43 Bragg, William Henry, 33, 34f Bragg, William Lawrence, 33, 34f Buenos Aires, 97–98, 98f Bunge, Hernan, 96–97, 97f C Calutron isotope separator, 28–29 Capacitor, 15 Carotid angiography, Cartesian geometry, 51–53, 52f Cathode rays, 16–17 Cerebrospinal fluid (CSF) anatomy, 3–4, 5f cisternogram, 5–6 metrizamide, 5–6 pituitary adenoma, 5–6, 6f, 7f pneumoencephalogram, 4–5, 6f vestibular schwannomas, 5–6, 7f Chadwick, James, 19–20, 20f Cisternogram, 5–6 Clinical neurology, 2–3 C model, 120f, 121, 121f, 122f Cobalt-60, 68–69, 70–71 Cockroft–Walton accelerator, 25 Compton scattering, 21, 22f Contraption, 25–27 Craniopharyngiomas, 77–78, 85–86, 86t CSF See Cerebrospinal fluid (CSF) Cushing, Harvey, 30–31, 30f Cushing’s disease, 30–31, 32, 92, 105–106 Cyclotrons, 27f animal experiments, 42–43 artificial radiation, 31 beam energy and RBE, 40–42, 42f beam margin definition, 40, 41f Bragg peak (see Bragg peak) contraption, 25–27 Cushing, Harvey, 30–31, 30f Lawrence, Ernest Orlando (see Lawrence, Ernest Orlando) Lawrence, John Hundale, 27–28, 29–31, 29f narrow beams, 44, 44f neutron therapy, 32 protons, 33–34 radiation, properties of, 37–38 radioisotopes, 31–32 rotational irradiation technic, 43 shoot through technique, 43, 44f Wilson, Robert, 33, 34f D Deuterium, 38 Digital subtraction angiography (DSA), 112, 113f Donner Radiation Laboratory, 27–28 Dose-planning system computerized images, 112–113, 113f DSA, 112, 113f fiducials, 112–113, 114f GAMMAPLAN, 115–116 KULA, 114–115 E Electricity amber, 14–15 battery, 15 capacitor, 15 Compton scattering, 21, 22f electric motor and dynamo, 16 electromagnetic radiation, 16, 21 131 132 Index Electricity (Continued) positively/negatively charged objects, 15 subatomic particles, 17 units, 21–23 vacuum tubes, 16–17 Electromagnetic radiation, 16, 21 Electron, 17 Electron volts (eV), 21–23 Elekta company, 99–100 Elektron, 14–15 F Fiducials, 112–113, 114f First gamma unit patient Arndt, Juărgen, 80, 81f Backlund, Erik-Olof, 80, 81f Backlund’s paper, 82 CSF, 80–81 gamma-thalamotomy, intractable pain, 82 postoperative pituitary adenoma, 82 radiothalamotomy lesion, 79–80, 79f rectangular beam-shaping collimators, 79–80, 79f spherical shape gamma, 82 stra˚lkniven, 83 Studsvik AB, 77–78 Forster, David, 97, 98f G Gamma Knife AVMS, 104–105 B model, 119–121, 120f Bunge, Hernan, 96–97, 97f, 128 C model advantages, 121 APS system, 120f, 121 Elekta and Scanditronix, 99–100 evolution, 96 Forster, David, 97, 98f, 128 gamma enhet/gamma unit, 83 helmets adapters attachment, 117–118, 119f attachment in close-up, 117–118, 119f couch, 117–118, 118f storage, 117–118, 118f Larsson and Lide´n principles, 68–70 cobalt sources, 69, 70f collimators, 69 dose, 68–69 radiation source, 69 radiation volume shaping, 70 RBE, 70 Leksell, Lars, 95–96, 127, 128 meningiomas, 106–107 metastases, 107 Nucletec gamma unit, Buenos Aires, 97–98, 98f Perfexion, 123f, 124–125, 124f, 125f pituitary region tumors, 105–106 plugging, 122f preparation first gamma unit, 71 gamma unit design, 72–74, 74f, 119f proton beam replacement, 68 radiation and high-energy beams, 67–68 Sheffield, 97–98 Sophiahemmet, 74 therapeutic team controversy, avoidance of, 130 functions of, 130 team members, 129 in United States, 100 vestibular schwannomas larger, 108–109 smaller, 108 GAMMAPLAN, 115–116 Gamma rays, 18–19 Gamma-thalamotomy, 82 Gustaf Werner Institute, 57–58 H Hormone-producing tumors, 93 Hypophysectomy, 38–39, 86t, 91 I International Cancer Research Foundation, 27–28 Isodoses, 86–87, 87f, 88 K Karolinska University Hospital, 85, 91 Kiloelectron volts (keV), 21–23 Kilovolts (kV), 21–23 KULA, 114–115 L Larsson, B€ orje, 58–60, 58f Lawrence, Ernest Orlando, 26f associates, 28–29 cyclotron 27-and 184-in magnet, 27–28 contraption, 25–27 financial support, 27–28 education, 28 Manhattan Project, 25–27 parents, 28 Index Lawrence, John Hundale, 27–28, 29–31, 29f Leksell, Dan, 49, 128 Leksell Gamma Knife (LGK), 82, 128 Leksell, Lars, 48f, 95–96 education and career, 48–49 family, 48 first radiosurgery cases, 54–56, 55f first radiosurgery paper, 53–54 stereotactic localization system, 49–53, 52f Leyden jar, 15 Linear accelerator, 25–27 M Magnesia, 13–14, 14f Magnesium oxide (MgO), 13–14 Magnet, 13–14 MEDLINE database, 103–104 Megaelectron volts (MeV), 21–23 Megavolts (MV), 21–23 Meningiomas, 8, 8f, 86t, 106–107 Metrizamide, 5–6 Microsurgery, Motala Verkstad (Workshop), 71–72, 72f N National Hospital for Nervous Diseases, 10 Neurological hospitals, 10 Neutron therapy, 32 Nucletec gamma unit, Buenos Aires, 97–98, 98f O Operating microscope (OpMi 1), Operating theaters, 10 Ophthalmoscopy, Otoscope, P Parkinson’s disease, 63, 79–80 Particle accelerators Cockroft–Walton accelerator, 25 cyclotron (see Cyclotrons) Perfexion, 123f, 124–125, 124f, 125f Physics history amber, 14–15 electricity (see Electricity) magnesia, 13–14, 14f radioactive substances, 18–20 subatomic particles, 17 Pituitary adenomas, 5–6, 6f, 7f, 86t, 92–93 Plain skull X-rays, 3–4 Pneumocisternography, Pneumoencephalography, Protons, 18–20, 33–34, 61–62, 63–65 R Radiation volume shaping, 70 Radiation X-rays, 18 Radioactive decay, 18–19, 19f Radioactive isotopes, 31–32 Radioactive substances, 18–20 Radionuclides, 68–69 Radiosurgery, 128–129 beam characteristics, 39–40 brain and CSF anatomy, 4, 4f, 5f carotid angiography, clinical indications, 38–39 Compton scattering, 21, 22f contrast studies blood vessels (see Blood vessels) CSF replacement studies, 4–7 cyclotrons (see Cyclotrons) definition of, 1–2 dose-planning (see Dose-planning system) EEG and analog EMG, electromagnetic radiation, 16, 21 Gamma Knife (see Gamma Knife) Leksell, Lars (see Leksell, Lars) operating theater limitations, 10 physical characteristics, 38 plain skull X-rays, 3–4 pneumoencephalography and pneumocisternography, radiation, 18–20 requirements, 1–2, 37–38, 47 Stockholm radiosurgery 1968–1982 (see Stockholm radiosurgery 1968–1982) Uppsala research (see Uppsala research) vacuum tubes, 16–17 vertebral angiography, Werner, Gustaf, 57–58 Radiothalamotomy lesion, 79–80, 79f Reflex hammer, Relative biological effect (RBE), 40–42 Relative biological efficiency (RBE), 70 Rockefeller Foundation, 27–28 S Scanditronix company, 99 Sheffield Gamma Knife Web page, 98f Shoot through technique, 43, 44f Short-wave radio, 28 Skull X-ray, 88–89, 88f Static electricity, 15 133 134 Index Stereotactic functional neurosurgery, 79–80, 79f Stereotactic localizing system, 49–53, 52f Stereotactic radiosurgery See Radiosurgery Stereotaxy, 49–53 Stockholm radiosurgery 1968–1982 computerized imaging, 90 craniopharyngioma, 85–86, 86t diseases arteriovenous malformations, 93 pituitary adenomas, 92–93 trigeminal neuralgia, 91–92 vestibular schwannomas, 93–94 dose-planning, 86–89, 87f, 88f, 89f LINAC, 91 SIRP, 91 stereotactic radiosurgery, 86, 86t Subatomic particles, 17 Sundqvist, Hans, 72 Swedish Institute for Radiation Protection (SIRP), 91 T The Svedberg Laboratory (TSL), 57–58 Tobias, Cornelius, 39, 39f, 40 Trigeminal neuralgia, 54, 86t, 91–92 U U model, 121 Units, 21–23 Uppsala research beam characteristics, 62–63 human brain, radiosurgery of, 63 proton radiosurgery, 61–62, 63–65 radiobiology experiments on brain, 60–61, 62 US Gamma Knife, 100 V Vacuum tube experiments, 16–17 Vertebral angiography, Vestibular schwannomas, 5–6, 7f, 93–94, 108 Volts (V), 21–23 W Werner, Gustaf, 57–58 Wilson, Robert, 33, 34f X X-rays, 3–4, 21, 54–55 Other volumes in PROGRESS IN BRAIN RESEARCH Volume 167: Stress Hormones and Post Traumatic Stress Disorder: Basic Studies and Clinical Perspectives, by E.R de Kloet, M.S Oitzl and E Vermetten (Eds.) – 2008, ISBN 978-0-444-53140-7 Volume 168: Models of Brain and Mind: Physical, Computational and Psychological Approaches, by R Banerjee and B.K Chakrabarti (Eds.) – 2008, ISBN 978-0-444-53050-9 Volume 169: Essence of Memory, by W.S Sossin, J.-C Lacaille, V.F Castellucci and S Belleville (Eds.) – 2008, ISBN 978-0-444-53164-3 Volume 170: Advances in Vasopressin and Oxytocin – From Genes to Behaviour to Disease, by I.D Neumann and R Landgraf (Eds.) – 2008, ISBN 978-0-444-53201-5 Volume 171: Using Eye Movements as an Experimental Probe of Brain FunctionA Symposium in Honor of Jean Buăttner-Ennever, by Christopher Kennard and R John Leigh (Eds.) – 2008, ISBN 978-0-444-53163-6 Volume 172: Serotonin–Dopamine Interaction: Experimental Evidence and Therapeutic Relevance, by Giuseppe Di Giovanni, Vincenzo Di Matteo and Ennio Esposito (Eds.) – 2008, ISBN 978-0-444-53235-0 Volume 173: Glaucoma: An Open Window to Neurodegeneration and Neuroprotection, by Carlo Nucci, Neville N Osborne, Giacinto Bagetta and Luciano Cerulli (Eds.) – 2008, ISBN 978-0-444-53256-5 Volume 174: Mind and Motion: The Bidirectional Link Between Thought and Action, by Markus Raab, Joseph G Johnson and Hauke R Heekeren (Eds.) – 2009, 978-0-444-53356-2 Volume 175: Neurotherapy: Progress in Restorative Neuroscience and Neurology — Proceedings of the 25th International Summer School of Brain Research, held at the Royal Netherlands Academy of Arts and Sciences, Amsterdam, The Netherlands, August 25–28, 2008, by J Verhaagen, E.M Hol, I Huitinga, J Wijnholds, A.A Bergen, G.J Boer and D.F Swaab (Eds.) –2009, ISBN 978-0-12-374511-8 Volume 176: Attention, by Narayanan Srinivasan (Ed.) – 2009, ISBN 978-0-444-53426-2 Volume 177: Coma Science: Clinical and Ethical Implications, by Steven Laureys, Nicholas D Schiff and Adrian M Owen (Eds.) – 2009, 978-0-444-53432-3 Volume 178: Cultural Neuroscience: Cultural Influences On Brain Function, by Joan Y Chiao (Ed.) – 2009, 978-0-444-53361-6 Volume 179: Genetic models of schizophrenia, by Akira Sawa (Ed.) – 2009, 978-0-444-53430-9 Volume 180: Nanoneuroscience and Nanoneuropharmacology, by Hari Shanker Sharma (Ed.) – 2009, 978-0-444-53431-6 Volume 181: Neuroendocrinology: The Normal Neuroendocrine System, by Luciano Martini, George P Chrousos, Fernand Labrie, Karel Pacak and Donald W Pfaff (Eds.) – 2010, 978-0-444-53617-4 Volume 182: Neuroendocrinology: Pathological Situations and Diseases, by Luciano Martini, George P Chrousos, Fernand Labrie, Karel Pacak and Donald W Pfaff (Eds.) – 2010, 978-0-444-53616-7 Volume 183: Recent Advances in Parkinson’s Disease: Basic Research, by Anders Bj€orklund and M Angela Cenci (Eds.) – 2010, 978-0-444-53614-3 Volume 184: Recent Advances in Parkinson’s Disease: Translational and Clinical Research, by Anders Bj€orklund and M Angela Cenci (Eds.) – 2010, 978-0-444-53750-8 Volume 185: Human Sleep and Cognition Part I: Basic Research, by Gerard A Kerkhof and Hans P.A Van Dongen (Eds.) – 2010, 978-0-444-53702-7 Volume 186: Sex Differences in the Human Brain, their Underpinnings and Implications, by Ivanka Savic (Ed.) – 2010, 978-0-444-53630-3 Volume 187: Breathe, Walk and Chew: The Neural Challenge: Part I, by Jean-Pierre Gossard, Re´jean Dubuc and Arlette Kolta (Eds.) – 2010, 978-0-444-53613-6 Volume 188: Breathe, Walk and Chew; The Neural Challenge: Part II, by Jean-Pierre Gossard, Re´jean Dubuc and Arlette Kolta (Eds.) – 2011, 978-0-444-53825-3 Volume 189: Gene Expression to Neurobiology and Behaviour: Human Brain Development and Developmental Disorders, by Oliver Braddick, Janette Atkinson and Giorgio M Innocenti (Eds.) – 2011, 978-0-444-53884-0 135 136 Other volumes in PROGRESS IN BRAIN RESEARCH Volume 190: Human Sleep and Cognition Part II: Clinical and Applied Research, by Hans P.A Van Dongen and Gerard A Kerkhof (Eds.) – 2011, 978-0-444-53817-8 Volume 191: Enhancing Performance for Action and perception: Multisensory Integration, Neuroplasticity and Neuroprosthetics: Part I, by Andrea M Green, C Elaine Chapman, John F Kalaska and Franco Lepore (Eds.) – 2011, 978-0-444-53752-2 Volume 192: Enhancing Performance for Action and Perception: Multisensory Integration, Neuroplasticity and Neuroprosthetics: Part II, by Andrea M Green, C Elaine Chapman, John F Kalaska and Franco Lepore (Eds.) – 2011, 978-0-444-53355-5 Volume 193: Slow Brain Oscillations of Sleep, Resting State and Vigilance, by Eus J.W Van Someren, Ysbrand D Van Der Werf, Pieter R Roelfsema, Huibert D Mansvelder and Fernando H Lopes da Silva (Eds.) – 2011, 978-0-444-53839-0 Volume 194: Brain Machine Interfaces: Implications For Science, Clinical Practice And Society, by Jens Schouenborg, Martin Garwicz and Nils Danielsen (Eds.) – 2011, 978-0-444-53815-4 Volume 195: Evolution of the Primate Brain: From Neuron to Behavior, by Michel A Hofman and Dean Falk (Eds.) – 2012, 978-0-444-53860-4 Volume 196: Optogenetics: Tools for Controlling and Monitoring Neuronal Activity, by Thomas Kn€opfel and Edward S Boyden (Eds.) – 2012, 978-0-444-59426-6 Volume 197: Down Syndrome: From Understanding the Neurobiology to Therapy, by Mara Dierssen and Rafael De La Torre (Eds.) – 2012, 978-0-444-54299-1 Volume 198: Orexin/Hypocretin System, by Anantha Shekhar (Ed.) – 2012, 978-0-444-59489-1 Volume 199: The Neurobiology of Circadian Timing, by Andries Kalsbeek, Martha Merrow, Till Roenneberg and Russell G Foster (Eds.) – 2012, 978-0-444-59427-3 Volume 200: Functional Neural Transplantation III: Primary and stem cell therapies for brain repair, Part I, by Stephen B Dunnett and Anders Bj€orklund (Eds.) – 2012, 978-0-444-59575-1 Volume 201: Functional Neural Transplantation III: Primary and stem cell therapies for brain repair, Part II, by Stephen B Dunnett and Anders Bj€orklund (Eds.) – 2012, 978-0-444-59544-7 Volume 202: Decision Making: Neural and Behavioural Approaches, by V.S Chandrasekhar Pammi and Narayanan Srinivasan (Eds.) – 2013, 978-0-444-62604-2 Volume 203: The Fine Arts, Neurology, and Neuroscience: Neuro-Historical Dimensions, by Stanley Finger, Dahlia W Zaidel, Franc¸ois Boller and Julien Bogousslavsky (Eds.) – 2013, 978-0-444-62730-8 Volume 204: The Fine Arts, Neurology, and Neuroscience: New Discoveries and Changing Landscapes, by Stanley Finger, Dahlia W Zaidel, Franc¸ois Boller and Julien Bogousslavsky (Eds.) – 2013, 978-0-444-63287-6 Volume 205: Literature, Neurology, and Neuroscience: Historical and Literary Connections, by Anne Stiles, Stanley Finger and Franc¸ois Boller (Eds.) – 2013, 978-0-444-63273-9 Volume 206: Literature, Neurology, and Neuroscience: Neurological and Psychiatric Disorders, by Stanley Finger, Franc¸ois Boller and Anne Stiles (Eds.) – 2013, 978-0-444-63364-4 Volume 207: Changing Brains: Applying Brain Plasticity to Advance and Recover Human Ability, by Michael M Merzenich, Mor Nahum and Thomas M Van Vleet (Eds.) – 2013, 978-0-444-63327-9 Volume 208: Odor Memory and Perception, by Edi Barkai and Donald A Wilson (Eds.) – 2014, 978-0-444-63350-7 Volume 209: The Central Nervous System Control of Respiration, by Gert Holstege, Caroline M Beers and Hari H Subramanian (Eds.) – 2014, 978-0-444-63274-6 Volume 210: Cerebellar Learning, Narender Ramnani (Ed.) – 2014, 978-0-444-63356-9 Volume 211: Dopamine, by Marco Diana, Gaetano Di Chiara and Pierfranco Spano (Eds.) – 2014, 978-0-444-63425-2 Volume 212: Breathing, Emotion and Evolution, by Gert Holstege, Caroline M Beers and Hari H Subramanian (Eds.) – 2014, 978-0-444-63488-7 Volume 213: Genetics of Epilepsy, by Ortrud K Steinlein (Ed.) – 2014, 978-0-444-63326-2 Volume 214: Brain Extracellular Matrix in Health and Disease, by Asla Pitkaănen, Alexander Dityatev and Bernhard Wehrle-Haller (Eds.) – 2014, 978-0-444-63486-3 ... kinds in its research, there was a period prior to the invention of these machines when other methods had to be used In a sense, knowledge about the relevant phenomena extends Progress in Brain. .. explanation 3.2.2 Brain and CSF Anatomy It is necessary to digress a little and explain some facts about intracranial anatomy The brain sits tightly enclosed within the skull but it is floating in a bath... the skull in the midline and is easy to visualize even on a plain X-ray Insertion of metrizamide into the subarachnoid space enables outlining the contours of a tumor in this region hearing nerve