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YNIMG-10548; No. of pages: 12; 4C: 5, 6, 8 NeuroImage xxx (2013) xxx–xxx

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Review Connectomic approaches before the connectome

Marco Catani a,⁎, Michel Thiebaut de Schotten a,b, David Slater c, Flavio Dell'Acqua c,d a Natbrainlab, King's College London, Institute of Psychiatry, Department of Forensic and Neurodevelopmental Sciences, London SE5 8AF, UK b UMR_S 975, CNRS UMR 7225, Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière, Groupe Hospitalier Pitié-Salpêtrière, 75013 Paris, France c Natbrainlab, King's College London, Institute of Psychiatry, Department of Neuroimaging, London SE5 8AF, UK d NIHR Biomedical Research Centre for Mental Health at South London and Maudsley NHS Foundation Trust and Institute of Psychiatry, King's College London, UK article info abstract

Article history: Connectome is a term with a short history but a long past. Since the origins of neuroscience the concept of a Accepted 20 May 2013 ‘map of neural connections’ has been a constant inspiring idea for those who believed the brain as the organ Available online xxxx of intellect. A myriad of proto-connectome maps have been produced throughout the centuries, each one reflecting the theory and method of investigation that prevailed at the time. Even contemporary definitions Keywords: of the connectome rest upon the formulation of a neuronal theory that has been proposed over a hundred Connectome years ago. So, what is new? In this article we attempt to trace the development of certain anatomical and Connection fi Diffusion physiological concepts at the origins of modern de nitions of the connectome. We argue that compared to Tractography previous attempts current connectomic approaches benefit from a wealth of imaging methods that in part Hodology could justify the enthusiasm for finally succeeding in achieving the goal. One of the unique advantages of con- Networks temporary approaches is the possibility of using quantitative methods to define measures of connectivity where structure, function and behaviour are integrated and correlated. We also argue that many contemporary maps are inaccurate surrogates of the true anatomy and a comprehensive connectome of the human brain remains a far distant point in the history to come. © 2013 Elsevier Inc. All rights reserved.

Contents

Introduction ...... 0 Early proto-connectome maps (Table 1) ...... 0 Modern cartography (Table 2) ...... 0 Contemporary and future connectomes between macroscopic metaphors and microscopic myths ...... 0 Acknowledgments ...... 0 References ...... 0

Introduction The same approach has been proposed to describe the complexity of the nervous system. Here, interactions between 86 billion of neurons The pattern of scientific investigation cannot be understood in could be defined using nodes, hubs, connections and their properties isolation: it must be set against the background of wider trends in quantified in terms of efficiency, centrality, global and local integration, the sciences, methodological advancements, and general culture of etc. (Bullmore and Sporns, 2009). There is also a general perception the time (Clarke and Jacyna, 1987). Social, biological, and technological that network analysis could bring us closer to a true understanding network models dominate contemporary approaches to complexity of the real working of the human brain and its disorders. Two (Egerstedt, 2011). Telecommunications, social networks, transportation recent multicentre research projects testify to the interest and logistics, molecular interactions, and metabolic pathways are just some commitment of the international scientific community to this endeav- examples in which network analysis is used to described complex our. The Human Connectome Project (http://www.humanconnectome. dynamics (Sporns, 2011; Strogatz, 2001). org)isa$40millionNIHfundedstudytomapthehumanconnectome in 1200 healthy subjects using large scale functional and structural imaging. The Human Brain Project (http://www.humanbrainproject.eu)is ⁎ Corresponding author at: Natbrainlab, PO50 Department of Forensic and Neurodevel- fl opmental Sciences, Institute of Psychiatry, King's College London, London SE5 8AF, UK. one of the agship projects of the European Commission that is likely to E-mail address: [email protected] (M. Catani). receive funding in the region of €1 billion for the ‘simulation of the

Please cite this article as: Catani, M., et al., Connectomic approaches before the connectome, NeuroImage (2013), http://dx.doi.org/10.1016/ j.neuroimage.2013.05.109 2 M. Catani et al. / NeuroImage xxx (2013) xxx–xxx entire human brain connectivity at a neuronal level and emulation of its to identify those steps needed to fill the gap between current computational capabilities’.WiththerecentannouncementofPresident connectome maps and the real underlying anatomy of the human Obama of a budget of possibly $100 million a year for the Brain Research brain. through Advancing Innovative Neurotechnologies (BRAIN) Initiative, this field of research will see an even greater expansion. Early proto-connectome maps (Table 1) This unprecedented support is in large part due to the development of new methods to image networks in the living human brain and the Aconnectomeisdefined by its nodes and connections, whose anato- computational capability of processing and storing large amounts of my and function have been varyingly defined throughout history, data. The connectome approach, although new in its overarching con- according to the predominant theoretical constructs and the latest meth- ception, represents the culmination of converging lines of research, odological advancements available at the time. For a long time the most each of which have developed over the course of many centuries popular representations of the brain and its functions consisted of (Tables 1 and 2). In this paper we attempt to trace timelines of those an- diagrams depicting a variable number of intercommunicating ventricu- atomical (both at the macro- and microscopical scale), physiological lar cells (Fig. 1). The ventricular theory was the direct result of the use and methodological advances that helped to generate brain maps and of brain dissections as originally proposed by Herophilus of Alexandria shape their evolution throughout history. Tables 1 and 2 describe in the fourth century BC and two centuries later by Galen (Clarke and some of the pivotal discoveries in neurosciences from the field of mi- O'Malley, 1996). In these maps nodes correspond to ventricular reser- croscopy, electrophysiology/computational sciences, and anatomy/ voirs or cells with specialised functions. These chambers communicate neuroimaging. These timelines are not intended to be exhaustive through a system of interventricular foramina and to peripheral organs but rather highlight only a number of key discoveries and develop- by means of hollow nerves. In these proto-connectome maps, essential ments that have some relevance to contemporary connectomic elements of contemporary connectome descriptions can be found. Im- approaches. Our aim is to give credit to pioneers and put current plicit to the ventricular theory was the anatomical differentiation and connectome projects into a wider context. The figures reproduced functional specialisation of ventricular cells communicating through a in the article are examples of historical ‘brain maps’ that can be network system. Further, brain functions were seen as emerging from considered as possible forerunners of contemporary connectomes. the dynamic and regulated exchange between hierarchically organised In the final part we try to take advantage of our historical survey ventricular cells.

Table 1 Milestones in the history of neuroscience from Renaissance to the end of 19th century. MICROSCOPY ELECTROPHYSIOLOGY/COMPUTATIONAL NEUROANATOMY/NEUROIMAGING

Hans and Zacharias Janssen invent the Arcangelo Piccolomini, distinguishes the medulla (i.e. 1590 Rene Descartes describes the reflex as a sensory- 1586 microscope 1649 white matter) and the cerebrum (i.e. grey matter) motor mechanism for involuntary muscle contraction Thomas Willis speculates on the sensory and motor Jan Swammerdam discovers that the mechanical 1660 1664 nature of ascending and descending projection Marcello Malpighi observes the cortex and stimulation of nerves produces muscle contractions 1666 describes ‘globules’ and ‘fibres’ pathways Antonius van Leewenhoek provides the first Viessens separates commissural fibres of the 1674 1684 corpus callosum from projection fibres of the detailed description of nerve fibres Isaac Newton suggests the electrical nature of centrum ovale 1713 nerve signal propagation Leonhard Euler gives a mathematical formulation of the 1736 Könegsberg Bridge from which originates the modern graph 1786 Felix Vicq d’Azyr, describes commissural and theory associative pathways 1791 Luigi Galvani publishes his work on ‘animal electricity’ and describes nerves as ‘pathways that conduct electricity’ Joseph Gall identifies different cerebral gyri and 1810 localises cerebral functions in the cerebral cortex 1803 Giovanni Aldini, applies electrical currents to mammalian brains to trigger motor responses Johann Reil describes several association tracts, 1809-12 including the uncinate, arcuate, inferior longitudinal fasciculus and cingulum 1819-26 Karl Burdach extends Reil's work and gives latin names to association tracts Jean-Baptiste Bouillaud demonstrates that speech Christian Ehrenberg, Gabriel Valentin and Carlo Matteucci measures an electrical voltage across 1825 1830s is localised in the anterior regions of the brain 1833-8 Jan Purkinje describe single populations of the cell membrane neurons 1839 Theodor Schwann proposes the cell theory for all living organisms Jules Baillarger describes the cortical layers Wilhelm Griesinger and Thomas Laycock develop the 1840 1843-45 and compares them to a Galvanic pile concept of ‘psychic reflex’ for higher cognitive functions 1848 Emile du Bois-Reymond discovers the action potential (negative Schwankung) Augustus Waller describes the ‘ Wallerian’ 1850 1850 Herman von Helmholtz measures the propagation degeneration of axons speed of the nerve impulse Rudolph Kolliker identifies fibres and cells Bartolomeo Panizza discovers the visual centre in the 1852 in the cortex 1855 occipital lobe 1860 Otto Deiters describes axonal and dendritic 1857 François Lauret and Louis Gratiolet propose the lobar processes division of the brain 1862 Carl Weigert develops the first myelin stain 1861 Paul Broca identifies an area for speech production Julius Bernstein obtains direct recording of the action 1867 Theodor Meynert describes interlobar 1868 variations in the cortical layering potential and its kinetics Theodor Meynert formulates the associationist 1870-85 1870 Gustav Fritsch and Julius Hitzig use electricity to localize theory of brain function motor regions 1873 Camillo Golgi discovers the ‘black reaction’ 1874 Carl Wernicke puts forward the first nerwork model Richard Caton records electrical activity from exposed 1875 of higher cognitive functions rabbit and mouse brains James Sylvester introduces for the first time the 1878 Vittorio Marchi develops a technique to trace Santiago Ramón y Cajal proposes the neuron mathematical term ‘graph’ 1886 1887 degenerating axons over long distances theory

1891 Heinrich Waldeyer-Hartz uses the term ‘neuron’ to indicate the functional unit of the nervous system 1896 Paul Flechsig obtains myelogenetic maps of the human brain and distinguishes primary from association areas 1897 Charles Sherrington coins the term ‘synapse’

Table 2 Milestones in the history of neuroscience in the 20th century. MICROSCOPY ELECTROPHYSIOLOGY/COMPUTATIONAL NEUROANATOMY/NEUROIMAGING Joseph Dejerine describes the topographic Julius Bernstein advances the hypothesis that the action 1901 1902 potential results from a change in the permeability of the distribution of fibres within the internal capsule axonal membrane to ions Ivan Pavlov discovers the conditioned reflex as an 1903 automatic form of learning Alfred Campbell publishes the first map of the 1905 brain divided into 17 cortical fields Luis Lapicque publishes a model of integrate-and-fire Korbinian Brodmann produces cyto- 1907 1909 neurons suggesting a threshold for firing architectonic maps of the brain Oskar and Cecile Vogt work on myelo- 1910 architectonic maps of the human frontal lobe 1918 Walter Dandy introduces ventriculography Constantin Economo and Georg Koskinas 1925 publish the most comprehensive 1927 Hans Berger records the first human EEG 1927 Egas Moniz develops cerebral angiography cytoarchitectonic maps Jacob Moreno presents the first sociogram as a tool to study 1933 and visualize patterns of interpersonal relationships 1935 Joseph Klinger describes a new procedure to perform blunt dissections of white matter tracts 1937 Wilder Penfield and Edwin Boldrev describe the motor and 1938 Ernst Ruska develops the electron microscope sensory homunculus in man 1942 Albert Coons proposes immunoflurescence staining. 1943 Warren McCulloch and Walter Pitts propose the first mathematical model of a neural network Felix Block and Edward Purcell independently 1946 Donald Hebb proposes a theory for synaptic plasticity and 1946 describe the NMR phenomenon for liquid and solid learning process Walle Nauta and Paul Gygax develop a new 1951 The first Positron Emission Tomography staining method for degenerating axons 1950s Alan Hodgkin and Andrew Huxley publish a mathematical 1952 scanners are developed model for nerve excitation

1959 Mountcastle and Powell identify the columnar organization of the cortex Intra-axonal tract tracing compounds are 1960s David Cohen develops MEG 1960-70 developed (e.g. horseradish peroxidase 1959 David Hubel and Torsten Wiesel describe oriented receptive fields in the cat's primary visual contex and radiolabeled amino acids ) 1970s Godfrey Hounsfield produces Computerised Tomography 1969-71David Marr and James Albus develop a neurobiological and computational theory of cerebellar function 1977 Hans Kuypers uses fluorescent axonal tracers 1973 Paul Lauterbur publishes the first NMR image Eduardo Macagno, uses a serial electron 1979 microscopy to map an isolated neuron in the 1980 First Clinical MRI scanner water flea 1985 Denis Le Bihan applies Diffusion MRI to the Electron microscopy is used to describe the first living human brain Jay McClelland and David Rumelhart apply parallel distributed 1986 complete connectomme of the C. elegans (302 1986 processing theories to cognitive psychology and cognitive neuroscience neurons) 1988 Jean Talairach and Pierre Tournoux publish the first atlas in a common space of reference Gabriella Ugolini introduces the use of viruses Tim Berners-Lee develops a new hypertext system that 1989 1987 as transneuronal tracers runs across the internet, the world wide web Duncan Watts and Steven Strogatz present a 1990 Seiji Ogawa describes the BOLD effect 1998 Rabies virus are used to study polysynaptic mathematical model to describe small world networks 1995 1994 Peter Basser develops diffusion tensor imaging neural networks 1999 First in-vivo human diffusion tractography reconstructions

The ventricular model had a long lasting influence despite the fact that white by certain lines. The cerebrum commences everywhere by convo- obvious experimental evidence of its fallacy emerged during the Renais- lutions and extends as far as the corpus callosum... sance. Leonardo da Vinci, for example, obtained a wax cast of the ventri- cles that was clearly against the classical representation of the This distinction has direct relevance to modern connectomics ventricular system (Pevsner, 2002). Similarly, Vesalius showed that the where hubs are located in the grey matter and connections in the ventricular anatomy described by Galen was questionable and its doc- white matter. This is particularly true for those approaches that use trine did not fitwiththeevidencefromdissections(Vesalius, 1543). neuroimaging and electrophysiological methods to map whole brain From the sixteenth century the ventricular theory co-existed with a networks at the macroscopic level. new spirit in science based on the experimental method (Galilei, 1638) The study of the white matter anatomy expanded in the seventeenth and the renewed belief of an intimate relationship between anatomy century when many scientists recognised that white matter contains fi- and function (Catani, 2007; Catani and Thiebaut de Schotten, 2012). bres whose trajectories could be followed and described if specimens Post-mortem dissection became the primary method of investigation of were carefully prepared ‘using all the necessary precautions’ (Steno, the nervous system and this led to important anatomical discoveries, 1669): among them the distinction between the ‘cerebrum’ (i.e. grey matter or cortex) and the ‘medulla’ (i.e. white matter) by Arcangelo Piccolomini …fibres must be disposed in the most artful manner, since all the in 1586: diversity of our sensations and movements depend upon them. We admire the contrivance of the fibres in each muscle, and ought still more Icallthecerebrum[greymatter]that whole ashen-colored body, to admire their disposition in the brain, where confined in a very small darkening from white, which very closely encompasses the medulla. space, each execute their particular offices without confusion or disorder. The medulla is the whole of the white and more solid body, which is concealed within the ashen-coloredone.Thusthecerebrumdiffersand From these anatomical studies a new view of the white matter is distinguished from the medulla bycolor,becausethecerebrumis emerged; no more a homogenous support structure around the ven- ashen-colored but the medulla is white; in consistency, because the cere- tricles, but rather a complex medium composed of tubular filaments brum is softer and the medulla a little harder and more compact; in loca- for the passage of fluid between central cells and peripheral nerves tion, because the medulla is in the middle of the cerebrum which wholly (Descartes, 1662). These connecting filaments were found to origi- covers it over; also the ashen-colored body is distinguished from the nate from the cortex (Malpighi, 1666), specialise in motor and

Please cite this article as: Catani, M., et al., Connectomic approaches before the connectome, NeuroImage (2013), http://dx.doi.org/10.1016/ j.neuroimage.2013.05.109 4 M. Catani et al. / NeuroImage xxx (2013) xxx–xxx

anatomy (Fig. 2,left)(Descartes, 1664). Others produced images that had the primary objective of displaying true anatomical findings (Fig. 2,right)(Vieussens, 1685). By now the concept of connectivity was implicit in the idea of fibres and nerves. Originally prompted by the ventricular theory, the study of the white matter pathways remained linked for a long time to a hydraulic physiology of the brain. After all if, according to the ventricular theory, cogitation emerges from the flow and passage of fluid through hollow fibres, an exact description of these pathways could reveal the mechanisms of brain function. With the progressive accumulation of new anatomical findings the ventricular theory evolved, with a shift from central ventricular specialisation of function to a compartmentalised system of individual gyri containing animal spirits (Willis, 1664): But a no less important reason and necessity for the twistings [gyri] in the brain arises from the distribution of the animal spirits. Since for the various act of imagination and memory the animal spirits must be moved back and forth repeatedly within certain distinct limits and through the same tracts or pathways, therefore numerous folds and convolutions of the brain are required for these various arrange- ments of the animal spirits; that is, the appearance of perceptible things are stored in them, just as in various storerooms and ware- houses, and at given times can be called forth from them. Hence these folds or convolutions are far more numerous and larger in man than in any other animal because of the variety and number of acts of the higher faculties… Fig. 1. The ventricular system represented in a drawing dating from about 1310 (reproduced from Clarke and Dewhurst, 1972). The five cells are named according to their specialisation of function: the most anterior cells are the ‘sensus communis’ (e.g. At the beginning of the nineteenth century brain maps of white mat- common sense) and the ‘ymaginatio’ (e.g. visual sense) connected to the eyes through ter connections became gradually more refined with differentiation of the optic nerves. Behind are the cell ‘estimativa’ and the cell ‘cogitativa’, the latter tracts into callosal, projections and association pathways. Individual as- connected to a fifth cell, the ‘vis memorativa’ located below the ‘vermis’ of the cerebel- sociation tracts were also identified and their anatomy described in de- ‘ ’ lum. Cognitive processes result from the passage of spirits from one cell to the other. tail (Burdach, 1822; Reil, 1809, 1812). The convergence of anatomical Also note the hierarchical arrangement of the cells with the visual sense acting as a major hub connected to three other cells and the eye, while the other cells are only advancements with the progressive ‘corticalisation of brain functions’ connected to either one or two cells. culminated in Gall and Spurzheim's organology theory (Fig. 3). They believed that the brain is the organ of the mind and itself is made up of multiple ‘organs’,tobeidentified with the convolutions (Gall and Spurzheim, sensory functions (Willis, 1664), and coordinate a wide range of be- 1810): haviours, from simple reflex responses to cognition (Descartes, 1664). Some of the maps of this period had little anatomical accuracy. The convolutions, as far as they constitute an organ, receive their fi- The figure produced by Descartes to illustrate the complexity of white bers from different regions… These fibres or fibre bundles have a con- matter connections, for example, was pictorial in its representation of stant and uniform direction, different however in each region; they a philosophical concept rather than a faithful portrait of the real form their own expansions and their own convolutions; they develop

Fig. 2. The beginning of the modern study of white matter connections based on methods for fibre dissection. Left) Descartes' (1664) representation of the intricate system of white matter passages in the human brain had little anatomical correspondence. Right) Vieussens (1684) used post-mortem dissections to identify white matter tracts and was the first to separate the centrum ovale composed of projection fibres from the commissural fibres of the corpus callosum, in this figure partially removed in the midline.

Fig. 3. Organology and phrenology according to Gall and Spurzheim (1810). Left) Lateral view of a human brain where different groups of gyri are indicated with progressive num- bering according to their functional specialisation (Organology). Right) Protuberances on the skull that according to the phrenological theory resulted from the progressive expansion of the underlying gyri. Please note the correspondence of the numbers between the two ﬁgures.

at different stages of life; their number varies greatly in different brain (Baillarger, 1840) and current was applied to the brain to kinds of animal… each organ is independent and acts by itself by elicit movement (Aldini, 1803). New recording methods were also the virtue of its own powers and it contains directly within itself the introduced to study the characteristics of the action potential in the proximate cause of the phenomena which it offers. muscles (Bois-Reymond, 1848; Matteucci, 1830) and peripheral nerve (Bernstein, 1868). By the mid-nineteenth century, the concept But their view, although very modern in some respects, fell into dis- of spinal reflex was already established. This was extended from the repute mainly for two reasons. First, organology failed to embrace new spine to the brain (Griesinger, 1843; Laycock, 1845)and,withthe ideas on the physiology of the nervous system based on experimental experimental work of Ivan Pavlov (1903), conditioned reflex became work of Galvani and Aldini (see below). Second, organology lost a basic aspect of physiological psychology. scientific credibility when Gall and Spurzheim later suggested that The second half of the nineteenth century witnessed also the explo- mental faculties are localised in well-developed cortical organs and sion of advanced methods for microscopy. In 1839 Schwann proposed concluded that larger organs leave greater impressions on the skull. the cell theory for all living organisms and many microscopists begun With their new Phrenological theory they hoped to ‘ascertaining the to describe new cells in the brain (Schwann, 1839). Kölliker divided his- several intellectual and moral dispositions of man and animal, by the tological features of the cortex into myelo- (i.e. the pattern of distribu- configuration of their heads’ (Gall and Spurzheim, 1810). Despite the tion of cortical fibres) and cytoarchitectonic (i.e. the pattern of cellular fast spreading of phrenological ideas and their large diffusion across distribution in the cortex) (Kölliker, 1859)andMeynertobserved the continents, others continue to work on alternative models. interregional variations of the cortical layering (Meynert, 1868). In particular the first half of the nineteenth century saw the Methods for fibre staining advanced even at a faster pace. The introduc- emergence of a new paradigm: animal electricity (Galvani, 1791). This tion, for example, of methods for myelin staining by Carl Weigert and sparked debates in Italy and Europe and propelled a new series of exper- Vittorio Marchi, and the development of the precision microtome for iments that signposted the origin of modern electrophysiology. The new the study of serial sections improved the visualisation of small fibres paradigm attracted illustrious figures from other fields and promoted in the normal and pathological brains (Bentivoglio and Mazzarello, cross-fertilisation between anatomy and physics. The layering of the 2010). Bernhard von Gudden perfected an experimental method in cortex, for example, was seen as an ‘electrical generator’ of the human animals whereby he could produce secondary degeneration and atrophy

Fig. 4. Cortical centers and connections in the late nineteenth century deﬁned using clinico-anatomical correlation and post-mortem dissections. Left) Cerebral centres in the human brain dedicated to motor, somatosensory and language functions as displayed in one of the most popular neuroanatomy textbooks of the time (Testut, 1897): I) writing centre of Exner; II) Broca's centre for speech; III) motor centre, lower limb; IV) motor centre, upper limb; V) motor centre, face and tongue; VI–VII) Dejerine's centre for reading; and VIII) Wernicke's acoustic centre for verbal comprehension. Blue and purple areas are zones of the association centres according to Flechsig (1896). Right) Dejerine's representation of the white matter tracts of the human brain responsible for language and reading (1895). Note that at that time the exact correspondence between centres and cortical projections was not well established.

Please cite this article as: Catani, M., et al., Connectomic approaches before the connectome, NeuroImage (2013), http://dx.doi.org/10.1016/ j.neuroimage.2013.05.109 6 M. Catani et al. / NeuroImage xxx (2013) xxx–xxx

Fig. 5. Microscopy applied to the study of microcircuits of the hippocampus. Left) Hippocampal histology according to Camillo Golgi, inventor of the reazione nera (i.e. black reaction) method in 1873. Right) Hippocampal histology according to Santiago Ramon y Cajal (1911). Cajal also used the black reaction and introduced new concepts derived from his anatomical observations, including the directionality of impulse propagation (here indicated by the arrows). of the nerve nuclei and their connections by removing the peripheral sequence of the white matter pathways in the human brain. Considering sense organs, such as the eyes, ears, or various cranial nerves (von that the projection tracts are among the first to myelinate, he was able Gudden, 1870). Constantin von Monakow an assistant of Gudden, contin- to trace the origin and course of the corticospinal tract and describe for ued the work of his mentor on the thalamic and motor projection fibres the first time asymmetry in its crossing (i.e. decussation) at the level of (von Monakow, 1897). Following ‘extirpation’ of circumscribed areas of the medulla (Flechsig, 1876). For many a true understanding of the ner- the cortex he was able to follow retrogradely the degenerating tract to vous system was possible only through a precise depiction of its connec- the thalamic nuclei and other subcortical nuclei. Von Monakow was tions (Dejerine and Dejerine-Klumpke, 1895, 1901; von Bechterew, 1900). also the first to draw attention to the effects of a lesion on other distant At the same time clinicians begun to apply their neuroanatomical in- regions of the brain, a mechanism that he called diaschisis (von sights to patients (Catani et al., 2012a). The clinical–anatomical correla- Monakow, 1914). Paul Emile Flechsig studied the developing pathways tion method replaced phrenology and became a popular investigation with his myelogenetic method consisting of staining myelin in brains to infer possible functional correlates of cortical areas (Bouillaud, 1825; of foetuses or newborns and mapping a chronological maturational Broca, 1861). Disorders of the nervous system were explained in terms

Fig. 6. Cortical myelogenetic maps and white matter projections according to Flechsig (1896). Left) Flechsig identiﬁed different areas according to their degree of myelination at birth. Primordial areas are already myelinated at birth and have some correspondence with primary sensory and motor areas (densely dotted red areas). Tertiary association areas myelinate after birth and correspond to large regions of the frontal, parietal, temporal and occipital lobes. Sparsely red-dotted areas show intermediate degrees of myelination at birth. Right) Flechsig was able to reconstruct the trajectories of the main projection ﬁbres from his myelogenetic maps.

Fig. 7. Early cytoarchitectonic maps of the human brain. Left) Campbell's division of the cortex in 17 fields according to the interregional differences in cortical cyto- and myeloarchitecture (1905). Right) Brodmann's maps according to purely cytoarchitectonic criteria (1909). Note that while Campbell believed that its areas had some functional correspondence (hence terms like ‘visuo-sensory’ and ‘visuo-psychic’), Brodmann rejected any correlation between individual areas and functional localisation. of either cortical damage or disconnection syndromes (Fig. 4)(Dejerine 1896), delineation of maturational trajectories of the long white matter and Dejerine-Klumpke, 1895, 1901). Behind these maps was the idea projection tracts (Flechsig, 1896)andimprovedlocalisationoffunctions that brain should be understood as a whole, a system of integrated and and associated symptoms (Campbell, 1905; von Economo and Koskinas, interconnected areas. This approach required a good degree of approxi- 1925). However, cartographers differed among them in the ultimate mation, often resulting in a trivialised transposition of complex anatom- objective of their work and disputed on whether it could be possible ical details into simplified diagrams (Catani and ffytche, 2005; Catani and to understand brain function from their cortical maps. Two schools of Mesulam, 2008). thought emerged. For many, cortical maps were primarily anatomical divisions without any inference on function. Surprisingly, among them was Korbinian Modern cartography (Table 2) Brodmann who was clearly disdainful of any functional localisation in specificcorticalareas(Brodmann, 1909): By the end of the nineteenth century two lines of investigation emerged from the field of microscopy. The first important development In reality there is only one psychic centre: the brain as a whole with was the detailed description of microcircuits (Fig. 5)(Golgi, 1873; Cajal, all its organs activated for every complex psychic event, either all to- 1893). Ramon y Cajal championed this approach and introduced impor- gether or most at the same time, and so widespread over the different tant concepts in neurosciences, including a set of fundamental biologi- parts of the cortical surface that one can never justify any separate cal laws of neuronal organisation. He described, for example, how the specially differentiated ‘psychic’ centres within this whole. shape of axons and dendrites are constrained by biophysical parameters such as cytoplasmic volume, space and conduction time. He also intro- Paradoxically, in contemporary cognitive neurosciences, Brodmann's duced the law of dynamic polarisation that identifies dendrites and maps have become the lingua franca of cortical localisation — numbers cell body as the main receiving structures of the action potential and ax- used universally as shorthand for a precise cortical locus and, in some onal terminations as the main output. The existence of these laws en- cortical fields, a precise functional role (Fig. 7). Brodmann's approach abled him to formulate the neuron doctrine and to infer directionality to clinico-anatomical correlation was shared by many other influential in signal flow between neurons (Cajal, 1911). figures of his time and had long lasting consequences, especially in the The second line of investigation attempted to produce whole-brain field of psychology. Those who insisted on approaching the brain func- maps based on the study of interregional variations of the cyto- and tion from an anatomical point of view were disparagingly referred to as myeloarchitecture of the cortex. The development of new staining the ‘diagram makers’ and localisation theory were given very little im- methods combined with painstaking observations of large numbers of portance (Head, 1926; Lashley, 1950). brain slices led to important landmark discoveries, including the identi- The second approach was based on the assumption that cortical fication of primary and associative areas of the brain (Fig. 6)(Flechsig, divisions derived from cytoarchitectonic or myeloarchitectonic could

Fig. 8. Cortical divisions of the human brain and corresponding clinical syndromes according to Economo and Koskinas (1925). Left) Distribution of the ﬁve principal types of neo- cortex in lateral surface of the human brain: 1. agranular, 2. frontal, 3. parietal, 4. granular, 5. polar. Right) Corresponding clinical syndromes (in German). Please note the attempt to localise not only neurological syndromes but also psychiatric conditions (e.g. ‘depressive’ vs ‘expansive’ mental disorders in the frontal lobe).

Please cite this article as: Catani, M., et al., Connectomic approaches before the connectome, NeuroImage (2013), http://dx.doi.org/10.1016/ j.neuroimage.2013.05.109 8 M. Catani et al. / NeuroImage xxx (2013) xxx–xxx reveal important functional divisions. This approach, pioneered by number of cells, their density, grouping in stripes and layers (Fig. 8). Baillarger, Meynert, Wernicke and many others, had as ultimate goal The atlas is a monumental work, which, despite being considered by the establishment of solid scientificbasesforananatomically-based many the definitive text on cortical cartography, never met the favour classification of psychiatric disorders (Baillarger, 1840; Meynert, 1868; of the scientific community. This is probably in part due to its encyclo- Wernicke, 1906). The work of these psychiatrists had a great influ- paedic proportions, the lack of clear boundaries between some of the ence on future generations. In Germany Paul Flechsig developed a smallest areas and possibly the general feeling against the ‘crazy paving’ method for staining myelinated fibres and was able to distinguish school of cortical research, which peaked shortly after (Le Gros Clark, areas according to the order of myelination during the perinatal 1952). development (Fig. 6). In England, Alfred Campbell combined cyto- By the mid-twentieth century the combination of histological and myeloarchitectonic observations with histological studies of methods with neurophysiological techniques applied to the animal patients with various disorders to produce a map of distinctive corti- brain provided cortical architecture with a precise functional meaning. cal fields in the brain of Homo sapiens and other primate species This approach, as exemplified in the work of Mountcastle and Powell (Fig. 7)(Campbell, 1905). Campbell's monograph was a monumental (1959) on the somatosensory cortex of the monkey and of Hubel and achievement for several reasons, the most important being the empha- Wiesel (1962) on the visual cortex of the cat, was based on the use of sis given to function. Campbell's project went beyond cytoarchitectonic single- or multi-unit recording, axonal tracing by means of microlesion cartography, attempting to integrate clinical, anatomical, and physio- or dye injection and combined with the cytoarchitectural description of logical evidence to provide a guide to function (ffytche and Catani, sections later cut from the same brain. Key principles of cellular organi- 2005). Indeed, Campbell's 17 cortical fields are labelled not by numbers sation and neuronal physiology were discovered, such as columnar or- but by function (e.g. ‘visuo-sensory’, ‘audito-psychic’, ‘olfactory’, ‘pre- ganisation of the cortex and oriented receptor fields. At the same time central motor’,and‘post-central somatosensory’). the use of disconnection procedures in the monkey, combined with be- The era of cortical mapping culminated with the work of Cecile and havioural studies, intracortical recording, and axonal tracing revitalised Oskar Vogt and Economo and Koskinas. By studying the variation of cor- a network approach to brain functions (Fig. 9)(Mishkin, 1966). New tical myeloarchitectonic, the Vogt's tandem identified more than 200 methods became available for the identification of single axons and areas, many of which represent subdivisions of the cytoarchitectonic their exact cortical projection and termination (Fink and Heimer, areas of Brodmann (Vogt and Vogt, 1926). Despite working four- 1967; Nauta and Gygax, 1951). By the end of 1960s novel powerful handedly on the project and relying on the help of other assistants, tracers were developed based on the active transport of proteins and they never finished their monumental project and their anatomical other elements along the axonal fibres. These methods require injection endeavour has remained incomplete for most of the temporal and occipital of tract tracers into a predetermined cortical or subcortical region of the cortex (Nieuwenhuys, 2013). In 1925 Economo and Koskinas succeeded in nervous system. Once injected, the tracers enter the neuron and are publishing a prodigious atlas containing the cytoarchitectonic analysis of transported from the body of the neuron to its terminations (i.e. anter- 107 cortical areas, for each of which quantitative measurements were ograde direction) or in the opposite direction (i.e. retrograde direction) recorded for variations in cortical thickness and volume, form, size, (Morecraft et al., 2009). Tracer compounds would differ for their ability

Fig. 9. Connectivity maps based on animal studies. One of the advantages of animal studies is the ability to use data obtained with different methods and directly test network-based models of brain functions using experimental approaches (e.g. disconnection lesions). Lower left) Leslie Ungerleider and Mortimer Mishkin used animal electrophysiology, axonal tracing and lesion studies to formulate a dual stream model of visual processing (lower left) (Mishkin et al., 1983). Right) Felleman and Van Essen's (1991) projectome of the visual system show- ing the hierarchical connectivity of the visual areas. One of the limitations of these approaches is the inability to quantify the strength of connectivity between different areas. This means that the arrows and lines in the diagrams could be representative of single axons or large bundles. Also these maps have been transposed to humans without a direct anatomical verification. Bailey and von Bonin (1951), for example (upper left) applied their findings from the monkey directly to the human brain without experimental verification. The use of tractography could help to identify equivalence and between species differences in the anatomy of these tracts (Thiebaut de Schotten et al., 2011, 2012).

Please cite this article as: Catani, M., et al., Connectomic approaches before the connectome, NeuroImage (2013), http://dx.doi.org/10.1016/ j.neuroimage.2013.05.109 M. Catani et al. / NeuroImage xxx (2013) xxx–xxx 9 to follow a predominantly anterograde or retrograde direction although dynamics (Sporns, 2013). A popular approach uses network analysis most classical tracers are bidirectional (Glover et al., 1986; Kuypers et frameworks based on graph theory (Fornito et al., 2013; Hagmann et al., 1977; Mesulam, 1982). The field evolved further with methods al., 2010). This special issue is entirely dedicated to neuroimaging that combined different tracers (e.g. several conventional compounds methods for mapping the connectome and we refer to other papers or conventional with viral transneuronal tracers) and multiple sites of for an in depth illustration of the advantages and limitations of this injection (Morecraft et al., 2009). These methods led to a greater approach. understanding of the main features of many cortico-cortical and However, it is important to bear in mind that neuroimaging is only cortico-subcortical pathways, such as feedback and forward organisa- one of many methods for mapping the connectome and an important tion, hierarchical arrangement, and parallel organisation (Felleman distinction should be made between those approaches that adopt and Van Essen, 1991; Mesulam, 1998). They also provided solid founda- neuroimaging for mapping whole brain networks and other methods tions for computational approaches to brain function. One limitation of that characterise the most detailed features of microconnections using these approaches to connectivity is the general assumption that find- advanced microscopy technology (Lichtman and Denk, 2011; Seung, ings from animals can be directly translated to humans. This view 2012; Sporns, 2011). Clearly for the two approaches the suffix-ome may be valid for sensory and motor functions but there is some doubt refers to different concepts, one related to the totality of the brain (i.e. that it may hold true for other aspects of cognition such as language. the ‘connectome’ as a map of the entire brain connections), the other Post-mortem methods for cortical mapping of the human brain have to the totality of all its constituents (the ‘connectome’ as the most de- also evolved significantly in the last two decades. Karl Zilles and collab- tailed description of the elements that form neuronal connections). orators, for example, have developed a number of methods for auto- Hence, the first approach provides a global overview (whole-brain) of matic cytoarchitectonic and receptor mapping of post-mortem human the principal brain networks at a macroscopic level (i.e. large-scale con- brains (Zilles and Amunts, 2009). The advantage of these maps is that nections or bundles), the second aspires to the most detailed description they are provided within a standard template of reference and can be of local networks at a micro- and nano-scale (e.g. single axons and den- used to guide, complement and integrate other in vivo imaging drites). While the first approach can only be achieved through data re- methods (Caspers et al., this issue). duction and oversimplification (i.e. connectome as a metaphor), the In contemporary neuroscience neuroimaging methods have inaugu- second may never realise for the entire brain (i.e. connectome as a rated a new era in the study of functional and anatomical connectivity myth). In the last paragraph we argue that the two approaches could in the living human brain. Although many methods are still in develop- converge at the mesoscale level, at least for post-mortem studies in the ment and their use is limited, especially in the clinical settings, some near future and perhaps in vivo in the long term. principles of brain function are emerging from their application to large population of subjects. PET and fMRI studies for example, showed Contemporary and future connectomes between macroscopic the existence of a ‘default mode network’ consisting a group of medial metaphors and microscopic myths and lateral regions that is active during the ‘resting state’, a condition in which the majority of the subjects engage in an introspective, Current approaches to brain mapping result from the coalescence self-directed stream of thought (i.e. similar to daydreaming) (Raichle of fast paced advancements in computing (data processing and stor- et al., 2001; Raichle and Snyder, 2007). A synchronous deactivation of age, software development, etc.), quantitative and statistical neuro- the default network areas is observed in the transition between the ‘rest- psychological testing, MRI capability (higher resolutions, plethora of ing state’ and the execution of goal directed tasks, including working sequences for structural and functional imaging) and computational memory, focusing attention to sensorially driven activities, understand- theories (Lichtman and Denk, 2011; Seung, 2012; Sporns, 2011; ing other people's intention (mentalising or theory of mind), prospective Dell'Acqua and Catani 2012). In post-mortem brains the use of auto- thinking (envisioning the future) and memory for personal events mated histological analysis combined with transmitter receptor (autobiographic memory) (Raichle and Snyder, 2007). Alteration of the distribution and microarray profiling is beginning to delineate a default network activation has been reported in functional imaging new landscape of human cartography where multiple information is studies of patients with neuropsychiatric disorders, such as autism and available for each area (e.g. cytoarchitectonic, receptor and gene schizophrenia (Broyd et al., 2009). expression) (Hawrylycz et al., 2012; Zilles and Amunts, 2009). This Another significant contribution from neuroimaging is the possibil- information can be applied to in vivo imaging using atlas-based ity of measuring cortical thickness in healthy subjects and patients approaches and correlated with differences in functional activity, dif- with neurological and psychiatric disorders. The use of this method on fusion connectivity and behaviour. This could lead for the first time to patients with progressive loss of language due to a primary neurode- multimodal brain maps that define interindividual variability among generative disorder (i.e. Primary Progressive Aphasia), for example, the general population and help in understanding not only neural has significantly contributed to expand the classical model of language mechanisms of normal cognition, but also identify vulnerable connec- networks based on stroke studies to regions of the anterior temporal tivity patterns in those at risk for mental illness, and predict treat- lobe and medial frontal cortex (Rogalski et al., 2011). Similarly ment response and recovery after injury (Bullmore and Sporns, tractography studies based on diffusion tensor imaging and spherical 2009; Jbabdi et al., 2007; Stephan et al., 2009). deconvolution are revealing the existence of novel tracts underlying Nevertheless, contemporary approaches based on brain imaging are frontal lobe functions (Catani et al., 2012b)andlanguage(Catani not without limitations. One risk of contemporary connectome maps is et al., 2005; Catani et al., in press). A fundamental contribution of con- to divert from the real functional anatomy of the brain and to follow in- temporary neuroimaging is related to the description of interindividual stead a path of their own as it happened before in other disciplines. The differences in brain connectivity and the possibility of quantifying field of artificial neural networks, for example, just after McCulloch and parameters that give indirect measurements of the functional and ana- Pitts proposed the first mathematical model for a neural network in tomical strength of connections between regions (Catani et al., 2007; 1943, quickly evolved into statistical and pattern recognition tools far Thiebaut de Schotten et al., 2011). The above examples are indicative removed from the action of complex neurophysiological mechanisms of the far reaching potential of neuroimaging methods and their ability subserving their biological counterparts (Rosenblatt, 1958). In the to give answers to questions that were not possible to address before. case of the connectome there are several factors that may contribute With the introduction of the concept of a brain ‘connectome’ the field to a similar outcome. Mapping methods, for example, are typically moved a step farther (Sporns et al., 2005; Hagmann et al., 2007). Here based on data acquired at low resolution (a few millimeters) with several the ambition is to define the overall structural and functional brain ar- distortions due to high background noise and field dishomogeneity. chitecture to understand how anatomical networks influence neuronal Signal derived from the MRI scans reflects an average information,

Please cite this article as: Catani, M., et al., Connectomic approaches before the connectome, NeuroImage (2013), http://dx.doi.org/10.1016/ j.neuroimage.2013.05.109 10 M. Catani et al. / NeuroImage xxx (2013) xxx–xxx which derives from the combination of complex biological features of the that holds the key to the real working of the brain and only a underlying tissue, thus making any interpretation of the results connectome map ‘of the brain in action’ will capture the anatomical, unspecificandoftenspeculative.Furtherthenumberofpassagesrelated electrophysiological and computational elements of those networks to the data processing introduces artifacts and distortions that are that characterise human cognition and behaviour. Although this may difficult to distinguish from the real structural and functional anatomy. seem a distant point, at the time of the submission of this paper a report This is particularly true for connectomes based on diffusion imaging published in Nature Methods reawakened our optimism. Researchers at where the limitations of both the tensor model and more advanced the Howard Hughes Medical Institute's Janelia Farm Research Campus methods (e.g. Diffusion Spectrum Imaging and High Angular Resolution in Ashburn, Virginia have been able to record activity across a whole lar- Diffusion Imaging) (Dell'Acqua et al., 2010; Dell'Acqua et al., in press-a; val fish brain, detecting 80% of its 100,000 neurons (Ahrens and Keller, Descoteaux et al., 2009; Tournier et al., 2007; Wedeen et al., 2012)may 2013). The imaging system relies on a genetically engineered zebrafish produce connectivity maps that do not reflect the real underlying anato- whose neurons make a protein that fluoresces in response to fluctua- my (Catani et al., 2012c; Hagmann et al., 2010; Jones et al., 2013; Wedeen tions in the concentration of calcium ions, which occur when nerve et al., 2012). cells fire. A system composed of a microscope and detectors records ac- With diffusion datasets acquired at higher spatial resolution (cur- tivity from the full brain. The neurons are visible thanks to the transpar- rently ~1mm) some of these limitations may reduce. In post-mortem ency of almost the entire non-neuronal tissue of the zebrafish. samples even higher resolutions can be obtained (Kleinnijenhuis et Potentially this system could show the dynamics throughout the al., 2012; Leuze et al., 2013; McNab et al., 2009) with the advantage nervous system while the zebrafish engages in different behaviours of direct validation with histology of tractography reconstructions and during learning paradigms. Certainly the journey from here to ap- (Takahashi et al., 2013; Dell'Acqua et al., in press-b). plication of similar methods in the human brain (perhaps with high res- Another risk is that the language used today in contemporary map- olution functional diffusion imaging) is a long one in the history to ping and analysis techniques can be ambiguous at times as it uses a ter- come. In the meantime setting up combined imaging and post- minology that alludes to anatomical properties when in fact it reflects mortem histology studies of the white matter, perhaps using cutting- only features of the derived maps or graphs. Thus, a distance between edge methods for network analysis at the axonal level (e.g. Polarised two nodes in a network described using graph theory is not equivalent Light Imaging or Clarity) (Axer et al., 2011; Chung et al., 2013)could to the axonal length between the neurons that constitute those nodes help us to validate our current structural methods and move more se- but is the minimum number of steps required to connect the two cure steps on the steep ascent of the connectome science. nodes, regardless of their physical distances (Bullmore and Sporns, 2009; Fornito et al., 2013). Similarly, the average length of streamlines Acknowledgments in tractography is not equivalent to the average length of the connecting tracts. Moreover, many apparently functional properties of the neuro- We would like to thank Richard Joules, Stefano Sandrone and the imaging networks (e.g. connectivity, synchrony, etc.) are mathematical other members of the NatBrainLab (http://www.natbrainlab.com) and statistical concepts rather than physiological. Therefore, concluding for their helpful advice on the manuscript. This work was supported that the brains of certain groups of patients have reduced connectivity by Guy's and St Thomas Charity and the NIHR Biomedical Research because of the reduced fMRI co-activation or shorter length of their Centre for Mental Health at the South London and Maudsley NHS tractography streamlines calculated from DTI scans could be incorrect. Foundation Trust. Today we are certainly in a better position to effectively integrate different neuroimaging modalities and complement structural and References functional findings. 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Please cite this article as: Catani, M., et al., Connectomic approaches before the connectome, NeuroImage (2013), http://dx.doi.org/10.1016/ j.neuroimage.2013.05.109