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To say that the white matter is but a uniform substance like wax in which there is no hidden contrivance, would be too low an opinion of naturea€™s finest masterpiece.
Counting roughly 100 billion neurons, the number of units in the human central nervous system is vast, but not particularly mind-boggling: you have many more blood cells1. Connectionist accounts of brain function have extensively contributed to contemporary commonly held beliefs.
Connecting these concepts of scale to measurement capabilities that have been developed in the past centuries, we can note that this conceptual reason is not the only consideration when opting for a macroscopic description.
Confronted with a suspected stroke, one of the primary diagnostic tools available to an emergency room physician is DWI. Convincing evidence for the cardinal importance of DWI to connectivi-ty, dona€™t you think? Contributing to the disambiguation and validation of in vivo diffusion MRI methods is the principal aim of this thesis. This thesis contains a triplet of introductory chapters that will prepare you for the quintet of research chapters.
In Chapter 3, the concept of how nuclear magnetic resonance can be used in MRI to probe tissue properties is introduced as well as how a three-dimensional image reflecting these properties can be acquired noninvasively.
Chapter 4 describes a newly developed approach to DWI tractography in the white matter of the brain.
The results established in Chapters 5 and 6 gave confidence in the approach of mapping cortical fibre architecture with diffusion imaging. The final research paper in Chapter 8 provides an excellent example of how old and new techniques can amplify each other.
To conclude, Chapter 9 summarizes the contributions to the field of connectional anatomy reported in the thesis.
This chapter will give an introduction on the methods and discoveries of brain investigators throughout the ages.
It is not the goal of this chapter to give a comprehensive account of the history of white matter research. The primary source of this chapter is the book a€?The Human Brain and Spinal Cord: A Historical Study Illustrated by Writings from Antiquity to the Twentieth Centurya€™ by E. The elements (earth, water, air and fire) and humours (blood, phlegm, yellow and black bile) of Hippocratic theory could already be recog-nized in Alcmaeona€™s ideas and are illustrative of the Greeksa€™ conception of the interactions between the external world and the body. Importantly, Plato, in the Timaeus (~360BC), also supported the cephalocentric view put forward by Alcmaeon. Unfortunately for posterity, the view of the brain as the centre of cognition faced heavy competition from the cardiocentric hypothesis.
Whereas cultural beliefs prohibited human dissections throughout antiquity, the Alexandrian Ptolemaic period was an exception.
During the Middle Ages, as in all branches of science and art, few new discoveries were made regarding the brain and its connections. The first scholar to make the distinction between the cortical grey and the underlying white matter (medulla) was Archangelo Piccolomini in 1586.
This discovery paved the way for other scientists to start unravelling the braina€™s connections. In the posterior portion of the brain, the distinction between various tracts has proven to be difficult to establish. The association tract connecting the frontal cortex with parietal association areas is the superior longitudinal fasciculus (SLF).
The fornix contains the efferent fibres of the hippocampus (which it leaves as the alveus, then fimbria) that project to the basal forebrain and the diencephalon.
The corona radiata contains fibres projecting from all over the hemispheres to various subcortical structures including the thalamus, brainstem and pontine nuclei. In the posterior part of the cerebral hemispheres, the sagittal stratum contains the visual projection system. The discovery of the heterogeneity of the white matter was followed by the observation of the laminated structure of the surrounding grey matter of the cortex.
The functional interpretation that was given to the discovery of the fibrous structure of the white matter by the Renaissance anatomists still leaned heavily on the Galenic view.
In the 19th century, the notions about brain function changed dramatically with the idea that specific mental functions were localized in specific areas of the cortex. The specificity of cortical localization by clinicopathological correlation was greatly enhanced by tract degeneration methods, for example those developed by Augustus Waller46. Some years prior to this, Bartolomeo Panizza already used the degen-eration technique to demonstrate that visual functions are located in the occipital lobe. Localization specificity was further enhanced by electrophysiological stimulation methods, although these could only be applied in animals and had a limited range with respect to the regions that could be investigated. One of the great scientific advances in history, the invention of the microscope, has benefitted neuroscience like no other tool has.
After the industrial revolution in the first half of the 19th century, Germanya€™s chemical industry was booming.
The LFB stain for myelin was developed by KlA?ver and Barrera; its combination with the cresyl violet counter-stain is referred to as the KlA?ver-Barrera method53. The debate that dominated neuroscience in the last decades of the 19th century concerned the structure of the brain network: is it continuous or is it built of units? Next to basic neuron morphology, the structure of the cortex (Box 2.3) was intensively investigated.
Meynert laid the foundations for the most significant neuroscientific endeavour of the first quarter of the 20th century. Although the investigative focus might have been on cyto-and myeloarchitecture of the cortex in the decades around 1900, white matter research was not abandoned. Paul Emil Flechsig investigated the sequence in which various fibre systems myelinate during pre- and postnatal development.
Around 1900, the couple Joseph Jules Dejerine and Augusta Dejerine-Klumpke published the perhaps most influential work on fibre systems in history67,68.
The cytoarchitecture, functional organization and fibre architecture of the primary visual cortex (V1) is visualized in the figure below. The opposite page lists the cytoarchitectural (left column) and fibrearchitectural (right column) particulars of the cortical layers (i.e. After World War II, tracing methods applied in living animals progressively improved, permitting highly specific connectivity research. The wealth of information on specific individual projections that these approaches have produced is most valuable when their interactions in the networks of the brain are considered. Technological advances have opened up avenues to investigate fibre architecture in the living human brain. After exposing an ensemble of excitable nuclei in a magnetic field to a second transverse magnetic field rotating at the appropriate frequency, the return to the equilibrium state is accompanied by detectable changes in the field.
The ground-breaking research on NMR was performed in the 1930a€™s and 1940a€™s, after quantum theory was developed. In MRI, we are we are generally not concerned with a single nucleus, but with a large set of nuclei of the same type, i.e.
In a spin system with spin quantum number $$I$$, the distribution of protons in the parallel vs.
The equilibrium magnetization vector $$\mathbf{M}_0$$ of the spin system in the presence of an external magnetic field $$\mathbf{B}_0$$ can be manipulated by supplying a magnetic field at the appropriate frequency. As the spin system is no longer in equilibrium after excitation, interactions of the protons with the environment will inevitably lead to a release of energy to return to the equilibrium state $$\mathbf{M}_0$$. While my assessment committee is reviewing a pre-print version of my PhD thesis I worked together with Alexander Gurten on the cover design. Scene 3, shows more and more learners are exchanging and leave trace in the Learning Network  in that way emerging paths are created from the bottom upwards (based on the behaviour of the learners).
Scene 4, larger and smaller emerging path and communities are created based on the personal needs of the learners. For sure there is plenty of space for alternative interpretations of the comic but that is what I actually like about it. Fortunately, I had read some books about negotiation (including Linda Babcock’s book that I list at the end), and I decided to give it a try.
The (surprising) reality is that your employer will see you as more valuable if you negotiate your offer, because part of the negotiation process is to emphasize what you are worth and the value that you bring to the company with your experience and skills.
Let’s say you accept an offer for $75,000, but you know others in the same geographical area are paid$80 -85000 for the same position. Many first time applicants have the attitude that they are so lucky to get the position, that they will just take it as is.
I worked in industry for several years and I know how much work goes into screening and interviewing candidates.
Clearly, you are worth a lot to this company, and they do not want to lose you.  In other words, the company views you as an asset, someone who brings value to the company, and your worth is probably more than your initial offer.
The bottom line is that you need to gather information as much information as you can about how much compensation someone in your position receives before you sit down to negotiate. Another candidate was offered a job at the beginning of the summer, but by that time she had booked a 2 week trip for the end of the summer.
To give you an example from academia, one successful candidate had to relocate to start a position as an assistant professor. In order to make this transition smooth, the assistant professor negotiated a 3-day weekends once a month for a year to be able to visit her husband, and no teaching assignment for the first year.
The most important thing about a BATNA is that you need to do the research before you negotiate – perhaps even before the offer.
The company wants you (remember how much they have invested in you) and if your requests are reasonable, they will probably do as much as they can to keep you.
As a first time job negotiator, it can seem intimidating to find the right words to negotiate an offer.
Some great thoughts, Dora (and thanks for mentioning our book.) The key piece of advice is to remember that the first offer is just that, the first offer. I love this topic because it can have an enormous impact and it is something that most people are uncomfortable with. Writing a PhD thesis can’t be compared to writing anything else, because there’s simply not another assignment like it. One of the greatest problems with PhD thesis writing is the simple fact of all the time and effort it takes up, two things which few students have to spare and some simply don’t have enough of to do a great job on the thesis. There are other services out there which you could hire to write your PhD thesis, but can you really trust such an advanced and difficult assignment to anyone but a professional with the extensive knowledge and experience to do a good job?
Hahn Institute for Magnetic Resonance Imaging in Essen, Germany and the Max-Planck-Institut fuI?r neurologische Forschung in KoI?ln, Germany. We are assured that wherever in the body there are fibres, they everywhere adopt a certain arrangement among themselves, created more or less according to the functions for which they are intended. The buzz-word is connectome: the matrix of structural links and functional associations between the basic units of the central nervous system3. For one, the construction of the comprehen-sive microscopic human connectome is far from within reach of neurosciencea€™s current technical capabilities.
Diffusion MRIa€™s ability to measure where cells are swollen (cellular oedema: a patholog-ical state) is critical for treatment decisions. To put matters back into perspective, the field of diffusion MRI for research is somewhat cloaked in a shroud of scepti-cism. In this chapter, it is explored whether fibre pathway reconstructions can be improved by integrating diffusion and susceptibility imaging, exploiting their respective advantages in angular and spatial resolution as well as their different contrast mechanisms.
Because recent high resolution diffusion MRI studies have shown radial fibre organization in the neocortex15,16, we set out to characterize the diffusion properties of the neocortex. The work is discussed in the light of recent advances and the probable future directions in the brain mapping community. Although the first mention of the brain is in the Edwin Smith surgical papyrus of which the original content is dated ~3000BC, we start our journey in Greek antiquity when the notion of the brain as an information-processing device first appeared. In this short sketch, it is unavoidable that many excellent scientists are, unjustly, left out.
For example, the elements of water and fire in the eyes were responsible for vision; air resounding in the auditory canal resulted in auditory perception. As Plato was not a naturalist, the resemblance of the head to the perfect figurea€”the spherea€”was his reason to adopt cephalocentrism. He made the subdivision on the basis of the macroscopic appearance of the tissue, describing the colour (ashen-coloured vs. The Enlightenment brought progress in all branches of science, including connectional neuroanatomy using the new tool of white matter dissection. The corpus callosum can be safely regarded as the most well known and investigated fibre bundle in the brain. On the midline, it is a small well-circumscribed cord of fibres wedged between the diencephalon and the columns of the fornix. It is well established that a projection system carries fibres from the thalamus to the visual areas and that this system is contained within the sagittal stratum.
It has three subcomponents (SLF I, II and III) distinguished over the mediodorsal-to-lateroventral axis18,33. It forms a continuous arc around the corpus callosum on the dorsal side and extends to the temporal lobe on the ventral side. The body of the fornix arches over the posterior part of the third ventricle separating anteriorly into the bilateral columns of the fornix and posteriorly into the bilateral crura. It is continuous with the internal capsule (red) that carries these fibres in between the lentiform nucleus laterally and the caudate nucleus and thalamus medially. It encapsulates the occipital horn of the lateral ventricle on all sides but the medial one. Naturally, the fibrous nature of the white matter fit in perfectly with being conduits (as in Alcmaeona€™s poroi) for animal spirits flowing on a€?a broad, almost a royal, highway a€¦ [which] are carried to all the nervous parts of the bodya€?40. Before these times, functional divisions that were made were crude and based on conjecture (e.g. Next to advancing the fruitful idea that the cortex is central to human brain function and providing descriptions of the cerebral white matter that still prove to be accurate today, Gall and his collaborator Johann Kaspar Spurzheim formed many of the misguided ideas of phrenology.
Many followed the holistic view of Jean Pierre Flourens, the most eminent scientist of the time.
The axonal degeneration by damage to a tract, sense organ or cortical area can be followed (anterogradely) through the white matter to its destination area. Panizza used both surgical ablation techniques in animals as well as human clinical observations to support his claim.
The initial successful investigations in electrophysiology have been performed by Eduard Hitzig and Gustav Fritsch50. The investigation of the microscopic structure of the nervous system has its origin in observations by Antoni van Leeuwenhoek, who described the bovine optic nerve as containing a€?filamentous particlesa€?51.
The availability of a wide range of dyes facilitated the discovery of chemical compounds suitable for staining biological materials for investigating them with a micro-scope.
The discussion was sparked by Joseph von Gerlach, who put forward the idea of the nerve net after observing a network of interlacing fibrils in his carmine-stained sections62. The preliminary microscopic examinations of van Leeuwenhoek and Malpighi were followed by the crucial macroscopic observations of Gennari and Baillarger, establishing that the cerebral cortex is a layered sheet. Cortical mapping became popular because it had been realized that the structural divisions found in the cortex were likely to be related to functional specialization of cortical areas (as discussed in Section 2.4).
Some of the most important principles of brain connectivity were uncovered during this period.
This myelogenesis method led him to some brilliant insights about connectivity and the nature of brain organization.
The Anatomie des Centres Nerveux contained the fruit of meticulous staining and serial sectioning of the human brain, building a near-comprehensive atlas of the white matter illustrated with many wonderfully accurate drawings. Before these methods became available, the Marchi method was reliant on myelin degradation and hence missed the (often unmyelinated) cortical extension of the axons. The hierarchy of the visual system of the macaque by Felleman and Van Essen72 is the famous example of a network-level description of tracing data. The most prominent methods for visualizing fibre systems in vivo are specific flavours of magnetic resonance imaging (MRI). NMR could only have been discovered in the age of quantum mechanics, because it uses manipulation of quantum states of the nuclei under investigation by exposing them to a magnetic field. Henceforth, the term proton will refer to the proton of the hydrogen atom 1H and will be used as the model system.
In the transverse plane, the magnetic moment vector describes a circular path: it is said to precess about $$\mathbf{B}_0$$. It is important to note for this thesis that the magnetization is directly proportional to the magnetic field, the proton density as well as inversely proportional to temperature.
Two relaxation mechanisms play a significant role in NMR: spin-lattice relaxation with time constant $$T_1$$ and spin-spin relaxation with time constant $$T_2$$.
Well, I really like comics and Alexander is an enthusiastic comic illustrator who lives in Berlin.  I had a scene in mind that demonstrates the emerging behavior of the underlying technology (collective intelligence, swarm-based theory, and collaborative filtering ) that I applied in my PhD research.
The base salary was much higher than what I earned as a postdoc and I finally had some real benefits. I was nervous when I called HR, but I told them the parts of the offer that I wanted to improve. By the time the company makes you an offer, they have screened possibly hundreds of resumes, phone-interviewed a dozen people, and called in 3-5 candidates for face-to-face interviews. Websites are a good source of information, but so are professional contacts who can give you more information about typical compensation packages. His company’s policy was they offered a relocation package if the commute was over 50 miles.
The relocation package was fantastic, but the problem was that her husband could not relocate right away because he had a private medical practice.
She later acknowledged that the university did not grant her everything on her wish list (regarding the start-up  package, for example), but she prioritized what was really important for her: being able to visit her husband once a month, and no teaching  for a year to allow her time to develop a research program. What is someone with your qualifications worth, and what is the minimum that you are willing to accept? However, if the #2 candidate was almost as qualified as you, then their BATNA could be to say “No” to your requests, even at the risk of losing you and then making an offer to the next candidate.

Some people call is a “gentle dance” as you and your potential employer go back and forth about what you would like and what they can offer you. I had never thought about negotiating over email, but I can see how some job candidates might try to do so, especially if they are afraid of the conversation. Negotiating salary is never easy, however, it is something that everyone should learn to do effectively.
Negotiating perks is often not thought about, but it is a great way to compensate for a salary that is less than you had hoped for. A really useful topic and article – especially for those where this might be their first time in this situation.
If you ask for a better offer you need to give a good reason of why you are worth more to the company.
We will visit scientists wielding their ever-improving tools to conquer the mystery of the brain. In line with Alcmaeona€™s beliefs, the Hippocratic School (~400BC) taught that the brain was responsible for sensation, emotion and intelligence.
Before Alcmaeon, this had been the dominant hypothesis for millennia in many cultures (e.g.
As a proponent of the empirical method, Aristotle paved the way for founding the Musaeum of Alexandria by his student Ptolemy I Soter23. Beside his anatomical, physiological and clinical observations, Galen has greatly advanced medicine by taking a definite experimentalist stance. Despite the strong influence of Galena€™s writings on medical issues, the cardiocentric view persisted throughout the Middle Ages. Displays of man-machine interactions form a popular means for commenting on current trends in society and artistic shock-effects are easily obtained by juxtaposing human anatomy with characteristically materialistic objects.
The anterior commissure tapers out to both sides over the inferior aspects of the temporal lobes. The anatomy of the associative systems in the occipital lobe, however, has seeded some controversies in the past.
The superior longitudinal fasciculus is thought to serve functions such as sensorimotor integration (SLF I), visuospatial awareness (SLF II) and imitation (SLF III). In the body of the fornix, part of the fibres cross to the contralateral hemispheres and hence the fornix is both a projection and commissural tract. Observed in sagittal view, it has the shape of a wedge with its apex in the brainstem and fibres a€?radiatinga€™ upward. Also Rene Descartes, in his Treatise of Man, adhered to the idea of animal spirits flowing through hollow fibres (tuyeaux) mechanically opened by the nerves. According to the phrenologists, hypertrophy or atrophy of cortical organs, and therefore mental faculties, could be measured by the morphology of the skull.
Refinement of the lesioning techniques at the turn of the 19th century allowed comprehensive descriptions of the gross anatomy of the visual system. Stimulating a doga€™s frontal lobes, they noticed the contractions of specific muscle groups on the contralateral half of the body. Carmine was the prime stain for the nervous system (used extensively by Joseph von Gerlach), colouring the cytoplasm a bright red. In ethanol solution, the saltsa€™ anion (copper phthalocyanine) binds to the cationic elements of the tissue. Important contributions in this respect were hardening the brain in alcohol59 or chromic acid60 and tissue fixation with formaldehyde61. His theory implied that dendrites, described 7 years earlier by Otto Deiters, formed a continuous network connecting all neurons63, while the axonal network was separate and more sparse. Using the newly developed histological tools, numerous neuronal cell types were discovered in the decades around 1900 (Purkinje cells, Betz cells, Cajal-Retzius cells; to name a few that are eponymous with their discoverers). Cyto- and myeloarchitectonic maps galorea€”with Alfred Walter Campbell, Grafton Elliot Smith, Korbinian Brodmann, Cecile and Oskar Vogt, and Constantin von Economo and Georg Koskinas as their most prominent inventorsa€”exhibiting a range of parcellation scales, taxonomies and claims.
Much of the basic knowledge of the white matter that can be found in textbooks can be traced back to investigators that had their productive years during this period. Flechsig not only determined important functional subdivisions within otherwise anatomically indistinguishable tracts (e.g.
Further, Jules Dejerine was an excellent clinician who classified many neurological syndromes for the first time69. The Bielchowsky silver impregnation was rather unpredictable, even after the improvements in the second half of the 20th century18. We can use this property to probe the excited nucleusa€™ environment that influences the process of return to equilibrium. Note, however, that most principles explained below can be applied to any nucleus with nonzero spin and charge such as 13C and 31P that are widely used in NMR spectroscopy.
For the present purpose, the collection of protons in the brain will be referred to as the spin system. As the orientation of the transverse component of the magnetic moment $$\mathbf\mu$$ is random for any proton, the spin system in equilibrium does not display net magnetization in the transverse plane.
For protons in the magnetic fields commonly used in NMR (1-30 T) and MRI (1-7 T) the resonance frequency is in the radiofrequency range and hence radiofrequency (RF) pulses are used for excitation of the protons.
In addition, if you are offered a new job another company their initial offer will be based on what you are making at your current job.
Perhaps not in the salary, but other factors such as start date, bonuses, vacation time, and flexible hours might be negotiable. Perhaps, there was a little good luck involved if you heard about the position by chance from a friend at the company who then forwarded your resume to the hiring manager. If the base pay does not cover your expenses or the job does not offer flexibility in their hours (which is a high priority for some) – then ask for what you need in order to make this job work.
I think the key is demonstrating to your potential (or current) employer the value you offer, and it’s important to do so first. In addition to possibly getting a better offer, negotiation s your opportunity to show you employer your qualifications and your value to the company. Writing a PhD thesis of this quality is remarkably difficult, though, you have to find a way to bring something new to your field in the most advanced and in depth way while still remaining concise, informative, and effective. There are many complex and difficult processes that you have to go through to complete a PhD thesis, and if you don’t stumble on one of them then you’re probably not human. You won’t find better PhD writing services to get help with your PHD thesis because we’ve got the caring and commitment that other services out there simply don’t, we know how difficult life as a student can be, and we’re simply here to make it a little easier and take a burden off your shoulders, so don’t argue and let us help!
We admire the skilful construction of the fibres in each muscle; how much more then ought we to admire it in the brain, where each of these fibres, confined in a small space, functions without confusion and without disorder. Nevertheless, people have come to realize that this approach falls short when the difficult questions are raised, in particular how the human brain sustains cognition and consciousness. Whether these subdivisions are justified with regard to phenomena to be explained is a matter of extensive debate4. For the work in this thesis, this entails DWI measurements of ex vivo tissue samples at a magnetic field strength much higher than customary for measuring human fibre anatomy in vivo.
The anatomical substrate of connections is tremendously relevant as it constrains this dynamic behaviour. Central concepts of fibre architecture in grey and white matter that have resulted from the efforts of the early neuroanatomical researchers is summarized in Boxes as a convenient reference for later research chapters.
More particular to this thesis, the specific opportunities and difficulties of ex vivo and high field (diffusion) MRI are discussed. Rather, the chapter aims to honour the efforts of the many contributors to the field by sketching the progress that has been made by leaps and bounds. It is a fine selection of passages (including a section on the cerebral white matter), commented with clarity, and providing an informative background on the quoted scholars. Whereas animals could only combine sensory information by correlation, the human brain was able to make inferences based on the sensory input to achieve understanding22. The Hippocratic stance on medicinea€”that illness was caused by imbalance of the humoursa€”was also applied to pathology of the brain. Democritus, who devel-oped the atomistic theory of matter, ascribed the smallest and most perfectly spherical atoms to the brain.
It was among this impressive gathering of scientists, that systematic investigations of human (neuro)anatomy were first undertaken between ~300-250BC. It was proposed by Nicolas Steno, first practiced by Thomas Willis and systematically applied by Raymond de Vieussens. What was regarded as the corpus callosum in the days of Galen (who named it) does not correspond with what is meant by it now.
It is a dynamic bundle that undergoes heavy pruning of connections during development leading to considerable variation in size between individuals. In short, the localization and existence of the inferior longitudinal fasciculus (ILF) and inferior fronto-occipital fasciculus (IFOF) has been a matter of debate (reviewed in Schmahmann and Pandya (2006)18, whose conclu-sions will be adopted here).
The arcuate fasciculus connects the caudal superior temporal lobe with the dorsal prefrontal cortex (in non-human primates). In cross-section, the convexities and concavities of the cerebral convolutions make them appear (inversely) u-shaped34, hence their name. They arise mostly from pyramidal neurons in the cingulate gyrus comprising association, projection (to the striatum) as well as commissural fibres. The sagittal stratum externa contains corticopetal fibres from the lateral geniculate nucleus of the thalamus.
The discovery was further generalized to multiple layers throughout the cortex by Jules Baillarger (1840)39. This position was rightly met with scepticism by most of the scientific community, but gained popularity in 19th century society nonetheless. Jean-Baptiste Bouillaud, Ernest Aubertin and Pierre Paul Broca adhered to localisationist theory. The degeneration method allowed Ludwig TA?rck to trace the divisions of the corticospinal tract in brain-damaged individuals47. Through clinocopathological correlations in brain-damaged World War I soldiers, this lay-out could be verified in humans as well. The method led to the first functional topographic map of an area of the brain and forms the basis of modern day electrophysiology. His cortical a€?glandsa€? in the grey matter were a first step in imaging microscopic brain structure. A differentiation step with lithium carbonate can remove weakly bound anions from the grey matter substance, while the stronger ionic bonds with the lipoproteins in the myelin sheet stay intact.
The silver is then replaced by metallic gold from a gold chloride solution (using oxalic acid as reductant), a process known as toning. A final indispensible ingredient for unravelling the microscopic structure of the neuron was the staining technique (Box 2.2). Camillo Golgi adapted von Gerlacha€™s nerve net theory, finding only evidence for the axonal network in his superior stainings, but becoming its greatest advocate nonetheless. The combination of the two opens the field of cortical cytoarchitecture: the anatomical study of the distribution of cell types over the cortical depth. In retrospect, it can be concluded that Brodmann a€?wona€™, because his map is most widely used today.
His wife Augusta, the first female intern in a French hospital, had the same gift topped with a heart for the injured soldiers of World War I70. The realization that active transport mechanisms in the cell could be used for delivery of a dye meant a leap in specificity and reliability in the 1970a€™s. The connectome of Caenorhabditis elegans has been mapped in its entirety with serial-section electron microscopy73. The technique is very versatile in its ability to characterize the microscopic magnetic environment of (water) molecules. They used inhomo-geneous magnetic fields to deflect spin-bearing nuclei in a molecular beam. An RF pulse is an oscillating magnetic field (the $$\mathbf{B}_1$$ field) transverse to the main magnetic field that tips the magnetization away from the z-axis when applied on-resonance (i.e. When you are offered a job, you are selected from a large group of candidates and the hiring manager and HR have invested a lot of time in making their decision. When you ask for a higher salary, you can refer to this information during your negotiation. He mentioned this to HR, and asked whether he could be compensated another way for his long commute. While the company did not grant her extra vacation, they did allow her to take her vacation time early (which was normally against company policy). While the situation was not ideal, it was clear that the couple needed to live apart for six months to a year in order for both of them to succeed professionally. All of these problems conspire to keep down the quality of your PhD thesis, they are the things that thesis writing students have been battling forever, but now with the help of our professional PhD thesis online writing services the thesis of your dreams is within your grasp. The organiza-tion of neurons in a network allows transmission, integration, storage anda€”perhaps characteristic for the human braina€”generation of information.
Even relatively straightforward questions about such topics cannot be answered without considering the interactions between the units. Fortu-nately, many investigators realize that the cumbersome anatomical work of past and present, as well as the structural connectome derived from diffusion MRI are indispensible ingredients in the mix of methods in order to draw sensible conclusions from functional data.
Chapter 2 also includes a brief overview of histological methods with a spotlight on the staining protocols used in Chapter 6 of this thesis. We arrive at modern day neuroscience equipped with the knowledge, experimental methods and thinking tools as they were accumulated over 2500 years. Furthermore, the aim is to create awareness that knowledge does not come from books, but from the people who have written and published books and papers over the past centuries.
Epilepsy, for instance, was demystified as the sacred disease by proposing blockage of the phlegm produced by the brain as its cause. A duo of highly knowledgeable physicians named Herophilus and Erasistratus have significantly advanced the field of medicine, and neuroanatomy in particular. This allowed him to gather a wealth of experimental evidence against the cardiocentric hypothesis, to which he was very strongly opposed. It is for this reason that anatomy was one of sciences at the forefront of the Age of Enlightenment. In the 17th century, the essential discovery about the nature of the white matter was that it is composed of fibres.
In the centuries after white matter dissection was first used, the method has been progressively refined by various pre-processing steps.
As no methods were invented to distin-guish bundles before the era of white matter dissection, the corpus callosum usually included the white matter mass within the hemispheres.
In mammals, the bundle is less important than in other vertebrates (that lack cerebral hemispheres and a corpus callosum).
The inferior longitudinal fasciculus is the visual association system connecting the extrastriate areas of the occipital lobe to the temporal lobe. Neighbourhood association fibres (neighbourhood SA) form the shell of fibres between the u-fibres and the deep white matter. The precommissural fornix (projecting to the septal nuclei and nucleus accumbens) is involved in emotional and motivational processing.
The internal capsule can be anatomically subdivided in an anterior limb, a genu and a posterior limb.
Phrenologists believed the cerebral convolutions to be the seat of certain propensities, sentiments and intellectual faculties.
In 1861, Broca provided the most convincing account that articulate speech functions are localized in the frontal lobe, likely on the inferior frontal gyrus, through autopsy of aphasia patient Monsieur LeBorgne, also known as a€?Tana€?45. Importantly, whereas white matter dissections are biased by expectations about the white matter anatomy in locations where fibre bundles cross, tract degeneration studies are not complicated by this at all.
It should be realized that many of these early observations are likely to have been artefacts owing to the limited accuracy of the tools. Improvement came with the silver staining method, perfected by Golgi, resulting in a a€?black reactiona€? for a small percentage of neurons in their entirety.
Interestingly, owing to the paramagnetic copper atom in the salt, the method also appears to work as a contrast agent for specific MRI applications54,55. With this methodological tripleta€”the microscope, tissue fixation, and dyesa€”the neuroanatomists of the second half of the 19th century were well equipped to tackle problems at the scale of the basic building blocks of the nervous system. However, consensus on an appropriate parcellation has never been reacheda€”and therefore investigators often choose a parcellation to suit their needs.

The subsequent development of many variants of the tracing methods resulted in enormous flexibility to answer experimental questions on connectivity pertaining directionality (retro- vs. The extensive collection of macaque tracing results in the CoCoMac database can nowadays be conveniently queried online74. By means of spectroscopy the physical and chemical properties of (organic) molecules can be investigated without obtaining information about the spatial distribution of the molecules. One of their important discoveries was that a discrete spectrum is obtained, which is direct evidence for a quantized angular momentum of the nuclei. That being said, some companies (or universities) will not increase your base pay even if you try to negotiate it. Universities usually publish their salaries and base packages and you can refer those if you want to negotiate an academic job. They also gave her the option of having one of those weeks unpaid, so she could still retain an extra vacation week for the following year. If you have another offer, you can mention the details of that compensation package and see this company can match it. The common mistake many make it discussing it way too early, without demonstrating any value first.
The method of tracing axons by injecting a label is highly specific and useful, but can only be used to investigate a small number of neurons per case. The methods used (high-field, ex vivo imaging using powerful gradient coils) present possibilities to not only demonstrate laminar characteristics, but to quantify cortical fibre architecture using advanced diffusion models.
Next to highlighting aspects of the anatomy not easily achieved with dissection, the combination with tractography of the same fibre bundles provides the link to modern-day clinical imaging methods, which is crucial to future radiologists, for example. His observation of poroi in the optic nerve suggests an empirical attitude, but it is debated whether he systematically applied the dissection technique.
Although the Hippocratic School rejected all superstition and embraced scrupulous clinical observation, there was little interest in anatomical observations and therefore no furtherance of neuroanatomy. Aristotle regarded the brain (amongst other organs) as a device to merely cool the hot organ of the heart.
Herophilus identified various cranial nerves and made the important distinction between motor and sensory nerve roots.
Galen is well known for his accurate and meticulous description of the ventricles, but he stressed the importance of brain tissue itself, contrary to a common belief that he originated the theory that the ventricles are the seat of the soul26. Already during the Renaissance, artists sought to improve their work by studying anatomy and practicing dissection. Using a rudimentary microscope, Marcello Malpighi traced white matter fibres from the brainstem to the cerebral hemispheres where he observed that they inserted into the cortex. Today, the corpus callosum is the arced set of fibres crossing the midline in the telencephalon. This position in phylogeny provides hints to its anatomical and functional significance in primates: connecting pre-isocortical and amygdalar regions of the brain and interhemispheric processing of emotionally and mnemonical-ly relevant visual and auditory stimuli18. Historically, the arcuate fasciculus has been regarded as a bundle connecting the language areas for articulation (Brocaa€™s) and comprehension (Wernickea€™s). As such, it is an important constituent of the limbic system, playing a central role in emotion.
The postcommissural fornix projects to the mammillary bodies of the hypothalamus and the thalamusa€™ limbic nuclei. The anterior limb includes mostly cortico-thalamic fibres from the anterior portion of the thalamus to the frontal lobe. A notable feature of the tract is the Flechsig-Meyer loop that curves through the temporal lobe in its course towards the lower bank of the calcarine sulcus. In Galla€™s framework, the cerebral convolutions were a€?expansions of the cerebral fibrils and of the fibre bundlesa€?43.
For example, the phrenologist George Combe located philoprogenitiveness (love of offspring) in the occipital pole, because the skull overlying this regiona€”the occiputa€”would be more prominent in primates and women44. The degeneration technique thus enabled Bernard von Gudden to describe intricate fibre crossings in the brain such as the optic chiasm48.
Significant progress was made after achromatic compound microscopes became available in the 1820a€™s. However, it should be noted that differentiation can be inhomogeneous and unverifiable in tissue blocks (as opposed to thin histological sections) used in ex vivo MR-microscopy55.
The silver protein oxidizes the metallic copper and both are reduced onto the section by hydroquinone. Building on Paul Ehrlicha€™s work on nerve endings, His deduced from the outgrowth of processes during cellular development that cells remained separate entities not in direct contact with each other64.
Next to providing the first detailed survey of the cytoarchitecture of the cerebral cortex, Meynert grounded the division of white matter into association, projection and commissural fibres as it is still used today. The major drawback of the active tracing method, however, is that it is not applicable in humans. Then, it provides a detailed description of the two MRI-methods sensitive to fibre architecture that are used in the remaining chapters of this thesis.
The magnetization can be tipped by an arbitrary flip angle α by using an appropriate RF pulse power. But as we will see, there are other parts of the compensation that you can negotiate, and sometimes they are even more valuable than your salary.
The network description at the neuronal levela€”the microscopic connectomea€”is comprehensive in terms of capturing potential information flow through the network of the brain. Knowledge on interregional connectivity in the human brain has been derived mainly from ex vivo cadaver dissections and clinicoanatomical correlations5. In addition, in Chapter 6 the ex vivo MRI results are validated with classical histological methods.
In the modern scientific discipline, we are often forced to look after personal short-term gains.
Furthermore, it is unknown whether Alcmaeon investigated multiple sensory pathways and traced the entire optical pathway from eyes to brain, or that he based his general conclusions on the excision of the eyeball alone22. In spite of rejecting the cephalocentric hypothesis, Aristotle still believed the brain to be an organ of primary importance to the whole body23. Erasistratus delivered a blow to proponents of the cardiocentric view by establishing the pumping function of the heart. He described the white matter structures of the fornix and corpus callosum (that included the white matter of the hemispheres). Anticipating the dawn of better times for science, the practice of human dissection was reinstated by Mondino de Luzzi at the turn of the 13th century27. The advent of tissue preservation methods with fixation chemicals brought new opportunities in the 19th century: the white matter dissections of Reil, Gall & Spurzheim, Burdach and Gratiolet demonstrated the fibre bundles and connections with much more clarity than the early efforts.
The putatively non-existent inferior fronto-occipital fasciculusa€”found by means of fibre dissection and MRI tractography, but not consistently in animal tracer studiesa€”would overlap with the inferior longitudinal fasciculus, or would be situated in between the sagittal stratum and inferior longitudinal fasciculus over its posterior extent.
Because there is little evidence that the bundle connects to Brocaa€™s area this is no longer tenable. The cingulum branches dorsally to multimodal sensory association areas and connects these to the limbic lobe. The posterior limb of the internal capsule includes many axons of the motor and sensory systems. Clinically, this anatomical peculiarity is relevant, because sectioning the loop in surgical treatment of temporal lobe epilepsy often leads to visual field defects.
These fibre bundles formed intra-hemispheric association tracts, both long- and short-range, that connected the various functionally specialized areas.
Notwithstanding the now obvious absurdity of these premises, the phrenological era does mark the start of investigations into the functional specialization of cortical regions.
For instance, in 1836 Robert Remak used it to accurately describe myelinated and unmyelinated nerve fibres. During the toning stage both silver and copper are replaced by gold, hence resulting in a more intense staining58.
This later became the well-known neuron doctrine, arguably the most influential doctrine in neuroscience today.
The ramification of these fibres in the cortical grey matter has been exquisitely described by RamA?n y Cajal. Isolated fire ants have a life expectancy that is 2-3 shorter than their well-connected cousins, and the principle generalizes to human society2! However, the neuronal scale might not be the optimal scale to study the brain for all questions raised. Hence, the interpretation of the DWI measurement in voxels with complex fibre configurations is inherently ambiguous. As it appears that ambiguity is inherent in the diffusion MRI measurement, the most promising validation approach employs independent measures of the same microstructure. It should not be forgotten that visionary insight requires the wisdom from the past as leverage for the achievements of the future. The animal dissections he performed allowed him a number of important neuroanatomical observations. Furthermore, his descriptions of the gross anatomy of the brain were unparalleled, describing the ventricles unabridged, and making a clear distinction between the cerebrum and cerebellum ascribing separate functions to each.
A final essential concept that emerges from his worka€”inspired by the concurrent investigations of physiology and anatomya€”is that structure and function are intimately linked. Although this is important in itself, his descriptions of neuroanatomy are rather obscure and no breakthroughs were achieved until the Renaissance anatomists took the stage. Vesalius, the exponent of the Renaissance anatomists, was a physician rather than an artist. A selection of these fibre bundles as they have been identified with dissection techniques is discussed in Box 2.1. The anatomical subdivision that is usually made in this massive fibre tract is over its rostrocaudal axis: the rostrum, genu, body and splenium of the corpus callosum contain interhemispheric connections of various lobes of the brain in a topographic manner. Anteriorly, the bundle would run ventral to the apex of the insula and alongside the fibres of the uncinate fasciculus to the ventral aspect of the frontal lobe. Because the bundle connects auditory regions to prefrontal areas it is now thought to be the auditory counterpart of the SLF II, serving audiospatial attention18. For example, damage to the diencephalic circuit seems to specifically impair memory recall, but not recognition37. Hence, the most common clinical symptom involving damage to the internal capsule is hemiparesis after lacunar infarction. The sagittal stratum interna contains the corticofugal fibres of the reciprocal pathway from visual cortex to the pulvinar of the thalamus and other subcortical structures. The association fibres included the commissures, but were distinguished from the projection system connecting cortical organs with subcortical structures and the spinal cord. Furthermore, his observations lead him to believe that the fibres were connected to the nerve cell, a year before cell theory was formed by Theodor Schwann in 1839. Over the past century, a plethora of staining methods have been proposed that have an affinity for various neural components.
Independent confirmation of the validity of the neuron doctrine came only three months later by August-Henri Forel. This forms the basis for the related field of myeloarchitectonics: the variation in myelinated fibre content over the depth of the cortex. We have arrived at the modern technique of tracking fibres in the human brain with diffusion MRI, the topic of the next chapter.
Bloch84 and Purcell, Torrey and Pound85 showed in 1946 that the same principles of excitation can be applied to liquids and solids.
Although all mechanisms reduce to the neuronal level, and ultimately the chemical and physical levels, the answers to questions asked on the phenomenological level might lose their explanatory power when given at the neuronal level, invoking the need for the mesoscopic (i.e.
Thus, it comes as no surprise that the development of a magnetic resonance imaging (MRI) technique to measure anatomical connectivity in the living human brain has been met with great enthusi-asm by the neuroscientific community. It is fairly well established, owing mainly to investiga-tions with diffusion MRI, that some psychiatric syndromes such as schizophrenia are associated with aberrant white matter microstruc-ture9,10. This is commonly known as the kissing-crossing problem, a term that does not quite capture the full extent of the problem as the ambiguity generalizes to a wider range of possible configurations. Microscop-ic measurements of fibre architecture in histologically processed tissue are the obvious candidate. Insightful conclusions about the anatomical and functional characteristics of the various major tracts are given in Part IV of the book, which also relates their findings to human anatomy (see Box 2.1). For example, he described two membranes covering the brain and gave a first account of its bilateral nature. An account of the relations between the parts of the nervous system was provided by Rufus of Ephesus (~100AD), who was heavily influenced by the Alexandrian scholars.
Nonetheless, he learned enough from Da Vincia€™s work to include his methods in his magnum opus from 1543: De Humani Corporis Fabrica28.
The last major advance in white matter dissection was made in the twentieth century by Ludwig Klingler, who invented loosening tissue structure by freezing and thawing the specimens after fixation. Memory systems are also linked by the cingulum: working memory in the dorsolateral prefrontal cortex, spatial memory in the parietal region and declarative memory in the hippocampal systems. The specialization hypothesis and the distinction between the fibre systems were largely based on correlations between observed brain damage with functional loss: the primary means to study functional specialization in that age.
A decade later, Wallera€™s degeneration studies established a functional division between the two, implicating the cell body as the trophic centre of the cells.
Using the very different approach of von Guddena€™s retrograde nerve degeneration studies, Forel showed that atrophy is confined to nerve cells with actual peripheral damage65. Several Nobel prizes have been awarded to the pioneers in both NMR (Isidor Rabia€ 1988, Felix Blocha€ 1983, Edward Purcella€ 1997) and MRI (Paul Lauterbura€ 2007, Sir Peter Mansfield), emphasizing the importance of the field.
The technique, introduced in the 1980a€™s6, is called diffusion weighted imaging (DWI; or diffusion MRI). Finally, experiments using tractography have led to important discoveries and new hypotheses in the field of brain connectivity. These approaches can serve as a bridge between the microscopic and macroscopic scales of connectivity. Part I is an historical overview like the present chapter, but with a length that cannot be accommodated in this thesis. In this form (Klingler dissection) white matter dissection is still practiced to date, for research purposes29, mapping surgical approaches30 as well as the preparation of educational specimens (this thesis, Chapter 8). The cingulum is furthermore implicated with internally oriented behaviour in linking the regions that make up the default mode network found with fMRI during the resting-state36.
The degeneration of the distal portion of a nerve fibre when detached from the cell body is still referred to as Wallerian degeneration. It is a stain well suited to investigate nuclear morphology and it gives a global impression of the cytoplasm. The final blow for nerve net theory came from Santiago RamA?n y Cajal, who provided yet another independent account of the unity of the nerve cell.
One popular way of defining what might constitute a functional area in the brain is the connectivity fingerprint. It complements early history with a stunning collection of reproductions of early white matter drawings and a summary of tracing studies of the twentieth century.
As such, the corpus callosum appears to be in-volved in the coordination of perception and action as well as interhemispheric cross-modality integration. A synthesis of the work relating to the debate was provided by Wilhelm Waldeyer, who gave the neuron its name66. The brain cellsa€™ microstructural constituents hinder diffusion of water molecules in the brain.
The principle assumes that neurons that share connections with the same regions are likely to serve the same function. The multiscale organization of the brain calls for a multilevel description, where the links between the levels are crucial for understanding how higher-level network properties emerge from the lower levels.
The primary source of the information in Box 2.3 is the neuroanatomy textbook by Nieuwenhuys, Voogd and van Huijzen19. Evidently, the functional significance of such a massive tract extends beyond perceptual and motor processes.
The often sad and irreversible consequence of connectional loss is a debilitating reduction in a braina€™s functional repertoire.
With tractography, plausible subdivisions on the basis of structural connectivity fingerprints have been produced for e.g. Furthermore, linking the body of microscale animal tract tracing literature to the now-feasible macroscale human investigations constitutes an important validation of the human structural connectome in its own right.
In fact, this book has been essential for most discussions concerning neuroanatomy throughout this thesis. On the other hand, just as specific interactions between individuals in human society can result in inspira-tional achievements, you can rest assured that you can achieve extraordinary things with this remarkable dynamic network of connec-tions 3.5 billion years of evolution has endowed you with. The collections of articles in Stricker and Power (1872)20 and Von Bonin (1960)21 provided English translations of influential papers from the early histologists and crucial publications on the human neocortex, respectively. Furthermore, the surgical procedure of callosotomya€”sporadically applied to relieve refractory epilepsy and resulting in a a€?split braina€™a€”has provided invaluable insights into hemispheric specialization as well as functional integration of mental processes32. Because the number of boundaries encountered in a particular direction depends on the orientation of axonal bundles7, it is possible to trace the major pathways in the white matter of the brain.
A further achievement in tractography is the possibility to construct the macro-scopic whole-brain structural connectomes alluded to previously. It has supported the relevance of the connectivity approach to brain function and spawned new hypotheses on global organizational principles of the brain. The progress that has been made in DWI and tractog-raphy has contributed significantly to the surge in connectionist approaches in cognitive neuroscience. To mention one example, the structural core of densely connect-ed areas that was discovered with diffusion MRI methods14 has been an influential notion in human brain connectivity research in recent years. Naturally, like any measurement technique, diffusion MRI has its limitations and some unresolved issues, but the practical utility for anatomical and pathological investigations in the human brain is undisputed.