From Early Pioneers to Recent Brain Network Findings

Biological Psychiatry: Review CNNI

Connectomics in Schizophrenia: From Early Pioneers to Recent Brain Network Findings

Guusje Collin, Elise Turk, and Martijn P. van den Heuvel

ABSTRACT Schizophrenia has been conceptualized as a brain network disorder. The historical roots of connectomics in schizophrenia go back to the late 19th century, when influential scholars such as Theodor Meynert, Carl Wernicke, Emil Kraepelin, and Eugen Bleuler worked on a theoretical understanding of the multifaceted syndrome that is currently referred to as schizophrenia. Their work contributed to the understanding that symptoms such as psychosis and cognitive disorganization might stem from abnormal integration or dissociation due to disruptions in the brain’s association fibers. As methods to test this hypothesis were long lacking, the claims of these early pioneers remained unsupported by empirical evidence for almost a century. In this review, we revisit and pay tribute to the old masters and, discussing recent findings from the developing field of disease connectomics, we examine how their pioneering hypotheses hold up in light of current evidence. Keywords: Association fibers, Connectomics, Dissociation, History of psychiatry, Integration, Schizophrenia http://dx.doi.org/10.1016/j.bpsc.2016.01.002

The hypothesis that schizophrenia is a disorder of brain connectomics in schizophrenia, Figure 1 shows a selection of connectivity has its roots in the 19th century, in which mental visionary scholars that contributed to the development of the illness was first attributed to the brain [for review, see (1)]. disconnectivity theory of schizophrenia. However, the methodological tools to test the disconnectivity Of note, the nomenclature in psychiatry has changed theory were long lacking, leaving it unsupported by neuro- substantially over the years (7). In the late 19th century, the biological evidence. Moreover, during most of the 20th term “amentia” (8) was used to refer to sudden-onset con- century, the world wars and the emphasis on psychology fusion with psychotic symptoms such as hallucinations and and psychoanalysis rather than biology hindered advances in catatonic features ranging from excitement to stupor. These neurobiological research of schizophrenia (2). The disconnec- patients shared many characteristics with those later tion theme reemerged in the late 20th century when neuro- described as suffering from dementia praecox (9) and schiz- imaging studies demonstrated connectivity deficits in the ophrenia (10,11). To avoid confusion, in this review, “amentia” disorder (3,4). In recent years, the application of graph theory and “dementia praecox” will be considered to refer to the to study the topological organization of the brain’s wiring clinical syndrome that is currently known as schizophrenia. network has provided a novel platform to study complex brain functions in both health and disease (5,6). These developments have inspired the notion that schizophrenia might best 19th CENTURY CONNECTIONISTS be understood as a connectopathy. Up until the 19th century, it was common to believe that This narrative review provides a chronological account of insanity came from (the) God(s) as a spiritual punishment for connectomics in schizophrenia. The earliest description of the sin and disobedience (12,13). This view started to change in clinical syndrome that would form the foundation for the the mid-19th century, when influential scholars such as Ger- modern concept of schizophrenia is usually attributed to Emil man neurologist and psychiatrist Wilhelm Griesinger (1817– Kraepelin. This well-known scholar and his contemporaries in 1868) argued that mental illnesses were disorders of the brain the field of mental illness and neural connectivity are used here (14). Under Griesinger’sinfluence, most of Western psychiatric as the starting point for our historical review. Using original research started to focus on the examination of anatomical papers, reviews, and biographies of these scientists, we trace and physiological properties of the brain (2,15,16). Griesinger’s the roots of the disconnectivity theory of schizophrenia apprentice, German-Austrian neuropathologist and anatomist throughout recent history. We integrate the historical narrative Theodor Meynert (1833-1892), maintained this direction. Using with an overview of current conceptions of connectivity and the newest methods of microscopic neuroanatomy, histology, connectome organization in schizophrenia and discuss how and brain preparation, Meynert worked on mapping the the ideas of pioneering connectionists hold up in light of cytoarchitecture of the cerebral cortex and the underlying current evidence. Paying tribute to the historical pioneers of white matter fiber tracts (17,18)(Figure 2). He was among the

SEE COMMENTARY ON PAGE

& 2016 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved. 1 ISSN: 2451-9022 Biological Psychiatry: Cognitive Neuroscience and Neuroimaging ]]] 2016; ]:]]]–]]] www.sobp.org/BPCNNI Biological Psychiatry: CNNI The History of Connectomics in Schizophrenia

Figure 1. Pioneers of schizophrenia and connectivity research. This ﬁgure shows early pioneers of connectomics and schizophrenia from the late 19th to the middle 20th century. Top row, from left to right: Wilhelm Griesinger, Theodor Meynert, Camillo Golgi, and Carl Wernicke. Middle row: Santiago Ramón y Cajal, the Alzheimer-Kraepelin lab (Alois Alzheimer, Emil Kraepelin, Robert Gaupp, and Franz Nissl), Emil Kraepelin, and Eugen Bleuler. Bottom row: the Vogt-Vogt lab (Cécile and Oskar Vogt and coworkers), Norbert Wiener, Karl Kleist, and Norman Geschwind. (Picture of Alzheimer-Kraepelin lab reproduced with permission from Kraepelin E, Hippius H, Peters G, Ploog D [1987]. The Memoirs. Berlin, Germany: Springer-Verlag. Other pictures reproduced under the creative commons license from wikipedia.org and fair use under copyright law from openlibrary.org.)

first to systematically classify white matter fiber tracts into disorders to disturbances of association fibers (19,20). For association fibers—interconnecting cortical areas—and pro- example, he argued that cell loss in the basal ganglia and jection fibers—carrying motor and sensory information to and associated functional disturbances of the projection fiber from the body. Linking these fiber tracts to brain disease, system might form the biological basis of the symptoms of Meynert proposed a dichotomy of brain disorders based on Parkinson’s disease and dementia (21), while disorganized the affected fiber class, attributing current-day neurological association fibers and associated disturbances in the cooper- disorders to projection fiber pathology and psychiatric ation between frontal areas and other parts of the brain could

2 Biological Psychiatry: Cognitive Neuroscience and Neuroimaging ]]] 2016; ]:]]]–]]] www.sobp.org/BPCNNI Biological Psychiatry: The History of Connectomics in Schizophrenia CNNI

association connections as the underlying cause of psychosis (24). He suggested that association fiber deficits could lead to abnormal activation of cortical sensory areas, resulting in symptoms such as hallucinations (24). Unfortunately, Meynert and Wernicke were never able to show histological evidence for disruptions in anatomical connectivity in schizophrenia, perhaps due, in part, to Wernicke’s untimely death from a bicycle accident in 1905 (25). It took almost another century before the development of diffusion-weighted imaging in the 1990s (26) and its application in schizophrenia from the year 2000 and onward [e.g., (27)] gave rise to the first evidence supporting their theories. Recent findings of affected fronto- temporal and frontoparietal connectivity in schizophrenia (27–29) testify to the prescience of Meynert’s and Wernicke’s theories that schizophrenia symptoms may stem from disruptions in the brain’s association fibers. Carl Wernicke thus contributed to the early development of the disconnectivity theory of schizophrenia, but—in contrast to Figure 2. Meynert’s pioneering work on white matter pathways. A drawing the acclaim for his pivotal work on aphasia—this contribution by Meynert of the brain’s major white matter fascicles, differentiating short is commonly overlooked. This may be due, in part, to the U-shaped fibers, and long association fibers:arcuate,inferiorlongitudinal, popularity of German psychiatrist Emil Kraepelin (1856-1926). uncinate, and cingulate fasciculi [Figure 3 from (145)]. F., frontal; In the sixth edition of his textbook (9), Kraepelin established a Occ., occipital; Tp., temporal pole. paradigm for psychiatry that soon spread the world (30) and laid the foundations for modern classification systems such as underlie amentia (11,20). This theory was further developed by the Diagnostic and Statistical Manual of Mental Disorders (31). his pupil, neuropathologist Carl Wernicke (1848-1905), who— Kraepelin sorted most of the recognized forms of “insanity” like his mentor—believed that mental disorders were caused into two major categories: dementia praecox and manic- by disturbances in the connections of the brain (15). Wernicke depressive insanity. He described manic-depressive insanity proposed one of the first models of integrative processing as a mood disorder featuring episodes of exacerbation among cortical areas as the neural basis for higher cognitive followed by remission or complete recovery. Kraepelin used functions such as language (Figure 3). There were major dementia praecox to refer to a progressive deterioration in developments in staining and fixation methods during the (cognitive) functioning, with the adjective praecox—meaning course of Wernicke’s career, mainly through the pioneering “early”—distinguishing the illness from dementia of the elderly. work of Camillo Golgi (1843-1926) and Santiago Ramón y In search of the underlying pathology of dementia praecox, Cajal (1852-1934). Together with Auguste Forel (1848-1931), Kraepelin collaborated with many well-known scientists. Dur- Golgi and Cajal were the first to argue that the brain consists ing his appointment as the chair of psychiatry at the University of neuronal cells that are connected to other neurons in of Heidelberg, he attracted neuroanatomists Franz Nissl different parts of the brain (22). These exciting developments (1860-1919) and Alois Alzheimer (1864-1915) to his depart- must have been part of the inspiration for Wernicke’s Sejunk- ment. When Kraepelin was appointed chair in Munich in 1903, tionshypothese (23) (from Latin sejungere, to separate). In this Alzheimer followed him there and worked with researchers hypothesis, Wernicke postulated a defect or interruption of such as Constantin Von Economo (1876-1931) [(32), from (33)],

Figure 3. Early models of neural integration as the basis for cognitive functions. Model by Wernicke (1874) of the language system (146) (left panel), further developed by Lichtheim in 1884 (87) (right panel). a, auditory input; A, auditory language region (Wernicke’s area); B, from German Begriff, referring to a broad set of concept representa- tions, thus involving distributed cortical brain regions and their collaboration (147,148); m, motor (speech) output; M, motor language center (Broca’s area).

Biological Psychiatry: Cognitive Neuroscience and Neuroimaging ]]] 2016; ]:]]]–]]] www.sobp.org/BPCNNI 3 Biological Psychiatry: CNNI The History of Connectomics in Schizophrenia

while Nissl remained in Heidelberg taking over Kraepelin’s is the real fundamental disorder appears to testify to an former position (34). About 10 years later, at the request of the intuitive notion that a disruption of the neural system that German Society for Psychiatry, Kraepelin explored the possi- allows synchronization among disparate brain regions may be bility of founding an Institute for Psychiatric Research, which central to schizophrenia’s pathophysiology, a notion that we was eventually established in 1917 and still exists today as the argue to be corroborated by modern studies showing dis- Max Planck Institute of Psychiatry. Upon the foundation of the proportionate disruptions of the rich club system and asso- institute, Nissl accepted an invitation from Kraepelin to join ciated changes in functional dynamics of the brain in him there, working alongside Korbinian Brodmann (1868– schizophrenia (50–54). 1918). Unfortunately, their collaboration was short-lived as Eugen Bleuler (1857–1950) offered a complementary view Brodmann and Nissl died shortly after one another, just 1 year on the pathophysiology of schizophrenia. It was Bleuler who after joining the institute (34). Together, these scholars proposed the term “schizophrenia” for the illness, derived from produced major scientific breakthroughs, mainly in neuro- the Greek skhizo (to split) and phren (mind). With this term, he degenerative disorders (2), including the first account of the referred to the split in cognition, perception, and personality histopathology of general paresis due to syphilis by Nissl (35) that he observed in his patients, rather than changes in brain and Alzheimer’s discovery of plaques and neurofibrillary anatomy. As opposed to Kraepelin, Bleuler objected to a tangles in (pre)senile dementia (36). At the conference where categorical view of schizophrenia, arguing that a healthy Alzheimer first presented these findings, his work received person may exhibit mild schizophrenic traits, while severe little interest (37), but Kraepelin recognized the fundamental traits are exclusive to patients (55). Bleuler suggested the core significance of Alzheimer’s observations (38). He included a disturbance to be a loosening of associations or “dissociation” description of the disorder in the eighth edition of his textbook (10,56), which may be argued to find its modern-day place in and proposed to call the illness Alzheimer’s disease (39). the Diagnostic and Statistical Manual of Mental Disorders as The relevance of these developments in the context of our disorganized speech. Such deficits in the train of thought current review is that Kraepelin assumed a similar biological resulting in incoherence are, in their most explicit form, basis for the cognitive decline in dementia praecox. In 1896, referred to as formal thought disorder. Or, as Bleuler described Kraepelin, Alzheimer, and Nissl developed the autointoxication it in his 1911 book [(10) cited from (57)]: theory, hypothesizing a degeneration of pyramidal cells in the second and third layers of the cortex in dementia praecox (40). The connections between associations are lost. The disease Reports of a decline in pyramidal cells in dementia praecox in interrupts the threads that give direction to our thoughts in an the 1920s (41) would add to the popularity of the theory, only irregular fashion, sometimes affecting only a few, sometimes a larger proportion of them. Thus, the result of the thought to be dismissed as technical artifacts after subsequent process is rendered unusual, and often logically incorrect. histological examination (42). Nevertheless, current postmortem evidence suggests that schizophrenia is associated with Bleuler assumed an underlying physical disease process smaller pyramidal cell bodies and decreased neuropil due, in but disagreed with Kraepelin as to the nature of this deficit. He part, to reduced spine density (43,44). These alterations are proposed that the pathology of schizophrenia was not neuro- best characterized in layer 3 of the neocortex, a major site for nal or cellular but one of conduction (56). From a modern-day corticocortical connectivity (44) that is thus crucial for estab- perspective, a conduction deficit might perhaps be interpreted lishing long-range communication between cortical areas (45). as referring to a disruption in functional connectivity for which Consistent with a deficit in corticocortical communication, there is now indeed strong empirical evidence in schizophrenia Kraepelin’s writings hint at a deficit in neural integration as part (50,58–60). As functional connectivity has been suggested to of schizophrenia’s pathophysiology. In his 1919 Dementia be shaped by the brain’s anatomical wiring network (61–65), Praecox and Paraphrenia [(40), cited from (46)], he writes (as there might be a common ground to both theories of the translated from German): disorder. Specifically, the disruptions in association fibers proposed by Meynert, Wernicke, and Kraepelin may form the … [ ] the organ of our psychic life must also contain mech- underlying substrate for a disturbance of the brain’s infra- anisms that mediate a general connection of all parts of the structure for integrative processing, invoking a functional psychic workshop among each other. Just the destruction of disorganization of associations as suggested by Bleuler. the psychic personality, of this inner harmony of all the parts Figure 4 provides a timeline of major developments in of the psychic mechanism in perhaps even surprisingly individual activities is, as formerly demonstrated, the real connectomics in schizophrenia from the middle 19th century fundamental disorder in dementia praecox. until today. Kraepelin thus assumed the brain to contain “mechanisms that mediate a general connection of all parts of the psychic 20th CENTURY DEVELOPMENTS workshop.” Emerging evidence from connectome studies now During the first half of the 20th century, psychodynamic suggests that these mechanisms may take the physical shape psychiatry gained ground over biologically oriented psychiatry. of a central connectivity core of highly connected hub regions Factors contributing to this development include the fact that (47–49). This anatomical rich club infrastructure is thought to despite claims that mental disorders are brain disorders, allow segregated functional systems to share information by empirical evidence to support a neurobiological basis for means of neural interaction. Without implying that Kraepelin mental disease was still lacking. This led to the dismissal of had a notion of brain hubs and their interconnectivity specif- neurobiologically oriented theories of schizophrenia as ically, his statement that the destruction of this inner harmony “Gehirnmythologie” or brain mythology (15). In addition, brain

4 Biological Psychiatry: Cognitive Neuroscience and Neuroimaging ]]] 2016; ]:]]]–]]] www.sobp.org/BPCNNI Biological Psychiatry: The History of Connectomics in Schizophrenia CNNI

Figure 4. Timeline of major developments in connectomics in schizophrenia. PET, positron emission tomography. research in Germany—at that time the epicenter of neuro- represented as an algorithm. This paper is now widely psychiatric research—was almost entirely shut down due to accepted as the basis for the central concept of the modern World War I. computer (75) and would be part of the inspiration for After World War I, there was a great demand for the American mathematician and philosopher Norbert Wiener’s treatment of mentally affected veterans. Veteran doctor Karl 1948 transdisciplinary work on control and communication in Kleist (1879-1960), a former pupil of Wernicke, developed a computing machines and the animal nervous system (76). functional atlas of the cortex based on the localization of Wiener thought of neural information as a form of online specific lesions in the brains of veterans (66) in combination memory, formed by impulses that travel along paths in the with functional stimulation and myeloarchitectonic mappings nervous system. Notably, he suggested neural trafficjams developed by Cécile (1870-1959) and Oskar (1875-1962) due to excessive occupation or the physical removal of Vogt (67). Kleist mapped these functional regions to the neuron chains (and associated rerouting of neuronal informa- detailed cytoarchitectural maps made by Brodmann and his tion) as a mechanistic explanation for mental illness. This scientific competitors of that time Von Economo and Georg theory may be the earliest conceptualization of disruptions in N. Koskinas. He tried to correlate damage in certain brain neural information flow and system dynamics as the under- areas to specificmentalsymptoms(68), a technique that lying substrate for mental disorders (77). would be further developed by his associates of the From 1950 onward, insights into the hereditary nature of Wernicke-Kleist-Leonhard School of Psychiatry (69). Kleist mental disorders and advances in treatment with antipsychotic argued that higher cognitive functions should result from medication (2) led to a return to neurobiology as the primary integration among cooperating systems, and he proposed focus of schizophrenia research, after years in which the affected collaboration between cortical and subcortical brain primary emphasis had been on psychology and psychoanal- regionsasthesubstrateofpsychosis(69,70), a theory that is ysis. Many of these developments were serendipitous; French now supported by modern-day findings of disrupted func- anesthesiologist Henri Laborit, for example, tried chlorproma- tional collaboration between brain regions in schizophrenia zine as an anesthesia adjunct and found it to produce (6,53,59,60,71–73). disinterest without loss of consciousness (78). He persuaded During and around the Second World War, the foundations doctors at the neuropsychiatric department of Val-de-Grâce were laid for the development of the modern computer, work military hospital in Paris to try the drug in a severely agitated that would prove crucial to the evolution of neuroimaging and manic-psychotic patient (79), who was found to be ready to computational connectomics. In 1936, mathematician and resume normal life after just 20 days of treatment (80). In the pioneering computer scientist Alan Turing (74)wrotea following years, the use of chlorpromazine spread quickly, paper in which he proved that a device that would become rapidly reducing episodes of violence and the number of days known as the Turing machine would be capable of perform- in seclusion in psychiatric hospitals throughout the world (81). ing any conceivable mathematical operation that could be During these years, the temporary setback of continental

Biological Psychiatry: Cognitive Neuroscience and Neuroimaging ]]] 2016; ]:]]]–]]] www.sobp.org/BPCNNI 5 Biological Psychiatry: CNNI The History of Connectomics in Schizophrenia

European research and the emergence of English as the processes under the influence of modulatory neurotransmitter dominant language of medical science led to a gradual neglect systems has been proposed as a central neurobiological of the works of early (mostly German-speaking) pioneers in mechanism in schizophrenia. This theory that is supported by neuropsychiatry (2,82). Behavioral neurologist Norman Gesch- evidence from recent genome-wide association studies impli- wind reversed this trend with his 1965 pivotal two-part cating genes involved in glutamatergic neurotransmission and monograph on disconnection syndromes in animals and man synaptic plasticity (110). (83,84), which inspired a resurgence of interest in disconnectivity as a pathophysiological mechanism for disorders of 21st CENTURY CONNECTOMICS higher cortical functions (85). Geschwind’s quotations and detailed summaries of connectivist accounts by early masters Since the development of imaging techniques capable of made the works of pioneers such as Wernicke (86), Ludwig capturing aspects of functional and anatomical connectivity, Lichtheim (87), Paul Flechsig (88), and Hugo K. Liepmann (89) the number of investigations of brain connectivity in schizo- accessible again to the neuroscientific community at large [for phrenia has been rising notably. A detailed discussion of these review, see (82–84)], thereby reviving the disconnection para- studies is beyond the scope of the current review, but their digm in language and cognitive-behavioral disorders. findings have been summarized in several excellent reviews It took an additional 20 years for positron emission [e.g., (6,27,59,104,111–114)]. These connectome studies build tomography studies to provide the first evidence for discon- on the premise that cognitive functions arise from neural nectivity in schizophrenia (3,90). Their findings were incorpo- interactions shaped by the brain’s connectional anatomy rated into the disconnection hypothesis, stating that (115). The way that the brain is wired is thought to drive how schizophrenia may best be understood in terms of affected neural elements exchange signals, how they encode sensory interactions between different cortical areas (4). Following information, and, ultimately, how the brain network as a whole initial findings, subsequent positron emission tomography coordinates complex neural phenomena underlying cognitive and electroencephalography studies (91–94)providedfurther processes (49). Indeed, studies have shown that connectome support for functional disconnectivity in schizophrenia. Indi- organization plays a role in cognitive functioning (29,116–118), cations for impairments in anatomical connectivity came from working memory performance (119,120), personality traits studies showing reduced white matter volume (95,96) (121,122), and creative thinking (123). The notion that (com- reduced white matter N-acetylaspartate signal intensity sug- plex) brain functions are not solely attributable to the proper- gestive of abnormalities in axonal connections (97)and ties of individual brain regions, but emerge from their interplay studies applying the (at that time upcoming) technique of within the connectome as a whole (5,50), implies that the diffusion-weighted imaging demonstrating reduced white brain’s wiring organization is crucial to healthy brain function, matter integrity in schizophrenia patients (98,99). In addition as well as to the manifestation of brain disorders to neuroimaging, evidence for disconnectivity on the (6,52,124,125). As previously alluded to, recent findings that cytoarchitectural scale includes reductions in dendritic spine long-distance association fibers of the brain’s central integration density (43,44,100,101) and abnormalities in oligodendro- system are particularly affected in schizophrenia (50–52)arein cytes and myelinated fibers (102,103). Notably, recent work line with Meynert’s and Wernicke’s hypotheses that schizophre- on the relationship between reductions in spine density and nia symptoms result from changes in the anatomical pathways macroscale connectivity suggests that regional disruptions in involved in higher-order association processes. With brain hub microscale neuronal connectivity in schizophrenia may be regions and their mutual connections forming an infrastructure related to the observed decreases in macroscale connectivity for interdomain functional integration (47,61), aberrant wiring of (45). In all, these findings converge on the notion that this system is consistent with global dysintegration [or malinte- schizophrenia involves disruptions in anatomical connectivity gration (13)] of neural information as part of schizophrenia’s from the synaptic to the whole-brain level and that these pathophysiology. Disproportional connectivity deficits of ana- deficits may be interrelated across spatial scales. tomical brain hubs and the rich club collective, as stated by Whether connectivity in schizophrenia is necessarily modern-day theories of schizophrenia (50), may provide con- reduced (disconnectivity) or more generally altered (dyscon- ceptual and empirical support for the long-standing notion that nectivity) remains subject to debate. We argue that the impaired neural integration is central to schizophrenia’s etiology. evidence for reduced anatomical connectivity is fairly con- Paraphrasing Wernicke [as translated from (24)]: sistent, and while both reduced and enhanced functional Let us designate this process of detachment with an appro- connectivity are reported, reductions in functional connec- priate name such as sejunction, and we cannot help to view it tivity tend to be reported more commonly (6,104). However, as a defect, a disruption of continuity, due to the failure of it is important to note that disruptions in structural con- associative functions. […] The very fact that the [schizophre- nectivity do not have to lead to reductions in functional nia] patient is unaware of the contradiction between his connectivity, as disinhibition and new neuronal interactions various delusions suggests that the integration of higher within disconnected networks may give rise to increased func- associations into one coherent whole […] has ceased to exist. tional interactions (6,105,106). In addition to impairments in anatomical connectivity as a possible cause for functional dysconnectivity, it has been argued that disruptions in func- CONCLUSIONS tional connectivity may stem from aberrant control of synaptic From early connectionists to current connectome findings, the transmission and plasticity (107–109). Specifically, dysfunc- long-standing hypothesis that schizophrenia symptoms may tional modulation of N-methyl-D-aspartate receptor dependent stem from a deficit in integrative neural processing due to

6 Biological Psychiatry: Cognitive Neuroscience and Neuroimaging ]]] 2016; ]:]]]–]]] www.sobp.org/BPCNNI Biological Psychiatry: The History of Connectomics in Schizophrenia CNNI

disruptions in the brain’s anatomical pathways for interregional 2. Wallace E, Gach J, eds. (2008): History of Psychiatry and Medical communication remains valid today. In recent years, emerging Psychology. New York: Springer Science 1 Business Media, LLC. findings from connectome studies have added considerable 3. Volkow ND, Wolf AP, Brodie JD, Cancro R, Overall JE, Rhoades H, conceptual and empirical support for malintegration as a Van Gelder P (1988): Brain interactions in chronic schizophrenics under resting and activation conditions. Schizophr Res 1:47–53. pathophysiological mechanism in schizophrenia. These stud- 4. Friston KJ, Frith CD (1995): Schizophrenia: A disconnection syn- ies point to a central role for hub pathology, including a drome? Clin Neurosci 3:89–97. reduced centrality of brain hubs and a disruption of rich club 5. Bullmore E, Sporns O (2009): Complex brain networks: Graph connections linking hubs together. theoretical analysis of structural and functional systems. Nat Rev Many questions and issues concerning the theory of schiz- Neurosci 10:186–198. ophrenia as connectopathy remain open. Among others, it 6. Van den Heuvel MP, Fornito A (2014): Brain networks in schizophrenia. Neuropsychol Rev 24:32–48. remains to be elucidated what the underlying neurobiology of 7. Houts AC (2000): Fifty years of psychiatric nomenclature: Reflections connectome disorganization and malintegration is, whether on the 1943 War Department Technical Bulletin, Medical 203. J Clin disconnectivity in schizophrenia is axonal or synaptic in nature Psychol 56:935–967. or both (71), and how changes in anatomical and functional 8. Meynert T (1890): Amentia, die Verwirrtheit. Jahrbücher für Psychiatr connectivity give rise to symptoms. Furthermore, the specificity und Neurol 9:1–112. of brain network findings discussed here and in other reviews 9. Kraepelin E (1899): Psychiatrie: Ein Lehrbuch fur Studirende und 6th ed. remains to be determined. For example, the overload and failure Aerzte, Leipzig, Germany: Verlag von Johann Ambrosius Barth. of brain hubs has been argued to be central to the etiology of all 10. Bleuler E (1911): Dementia Praecox oder die Gruppe der Schizo- fi brain disorders (126,127), while other ndings suggest that rich phrenien. Leipzig, Germany: Aschaffenburgs Handbuch, Deutike. club disconnectivity may be relatively specifictoschizophrenia 11. Shorter E (2005): A Historical Dictionary of Psychiatry. New York: (128,129). Oxford University Press, Inc. Using scholars from 19th century Western Europe as the 12. Fink PJ, Tasman A, eds. (1992): Stigma and Mental Illness. starting point of our historical inquiry, our review is European- Washington, DC: American Psychiatric Press. 13. Burns J (2007): The Descent of Madness. Evolutionary Origins of centric, no doubt bypassing crucial historical developments in Psychosis and the Social Brain. New York: Routledge. the rest of the world. In addition, there are exciting new directions 14. Griesinger W (1845): Pathologie und Therapie der psychischen in the field of disease connectomics that are not discussed in Krankheiten. Stuttgart, Germany: Adolf Krabbe Verlag. detail here, including effective connectivity studies exploring 15. Marx O (1970): Nineteenth-century medical psychology: Theoretical cognitive deficits and aberrant perceptual inference (130–132); problems in the work of Griesinger, Meynert, and Wernicke. Isis 61: the use of mathematical models to probe the developmental 355–370. origins and functional consequences of altered brain network 16. Marx O (1972): Wilhelm Griesinger and the history of psychiatry: – A reassessment. Bull Hist Med 46:519. topology (133 137); efforts to bridge the gap between genetic, 17. Meynert T (1865): Anatomie der Stirnrinde und ihre Verbindungs- cellular, and molecular pathology and large-scale connectomic bahnen mit den empfindenden Ober-flächen und den bewegenden disturbances (138–141); and attempts to use connectomics for Massen. In: Leidesdorf M, editor. Lehrb der Psychiatr Krankheiten, early detection and personalized prediction (141–144). These 2nd ed. Erlangen, Germany: Ferdinand Enke, 45–73. developments hold the promise of an increased understanding of 18. Meynert T (1867): Der Bau der Grosshirnrinde und seine ortlichen schizophrenia’s pathophysiology and will hopefully one day Verschiedenheiten, nebst einem pathologisch-anatomischen Corol- – contribute to one of the most pressing issues in schizophrenia larium. Vierteljschr Psychiat 1:77 93. 19. Seitelberger F (1997): Theodor Meynert (1833-1892), pioneer and research, early recognition and treatment of the emerging illness. visionary of brain research. J Hist Neurosci 6:264–274. 20. Pappenheim E (1975): On Meynert’s amentia. Int J Neurol 9: 311–326. ACKNOWLEDGMENTS AND DISCLOSURES 21. Haas L (1999): Theodor Meynert (1833–92). J Neurol Neurosurg M.P. van den Heuvel is supported by a Veni Grant (No. 451- Psychiatry 66:330. – 12-001) from the Netherlands Organization for Scientific 22. Golgi C (1967): The Neuron Doctrine Theory and Facts (Lecture delivered December 11, 1906). In: Nobel Lectures, Physiology and Research and an MQ fellowship (www.joinmq.org). Medicine 1901–1921. New York: Elsevier. The authors report no biomedical financial interests or 23. Wernicke C (1899): Psychiatrie, 1st ed. Leipzig, Germany: Barth. potential conflicts of interest. 24. Wernicke C (1906): Grundrisse der psychiatrie. Leipzig, Germany: Thieme. 25. Pillmann F (2007): Carl Wernicke and the neurobiological paradigm ARTICLE INFORMATION in psychiatry. Acta Neuropsychol 5:246–260. 26. Moseley ME, Cohen Y, Kucharczyk J, Mintorovitch J, Asgari HS, From the Department of Psychiatry, Brain Center Rudolf Magnus, University Wendland MF, et al. (1990): Diffusion-weighted MR imaging of Medical Center Utrecht, Utrecht, Netherlands. anisotropic water diffusion in cat central nervous system. Radiology Authors GC and ET contributed equally to this work. 176:439–445. Address correspondence to Guusje Collin, M.D., Ph.D., University 27. Ellison-Wright I, Bullmore E (2009): Meta-analysis of diffusion tensor Medical Center Utrecht, Department of Psychiatry, Brain Center Rudolf imaging studies in schizophrenia. Schizophr Res 108:3–10. Magnus, Heidelberglaan 100, 3508 GA Utrecht, PO Box 85500, Utrecht, 28. Van den Heuvel MP, Mandl RCW, Stam CJ, Kahn RS, Hulshoff Pol Netherlands; E-mail: [email protected]. HE (2010): Aberrant frontal and temporal complex network structure Received Nov 4, 2015; revised Jan 15, 2016; accepted Jan 19, 2016. in schizophrenia: A graph theoretical analysis. J Neurosci 30: 15915–15926. REFERENCES 29. Zalesky A, Fornito A, Seal ML, Cocchi L, Westin C, Bullmore ET, 1. da Mota Gomes M, Engelhardt E (2012): Meynert and the biological et al. (2011): Disrupted axonal fiber connectivity in schizophrenia. German psychiatry. Arq Neuropsiquiatr 70:894–896. Biol Psychiatry 69:80–89.

Biological Psychiatry: Cognitive Neuroscience and Neuroimaging ]]] 2016; ]:]]]–]]] www.sobp.org/BPCNNI 7 Biological Psychiatry: CNNI The History of Connectomics in Schizophrenia

30. Leonhard K (1985): Wernicke’s Psychiatry in Contrast with Kraepe- 57. Maatz A, Hoff P, Angst J (2015): Eugen Bleuler’s schizophrenia—a lin’s Psychiatry. In: Pichot P, Berner P, Wolf R, Thau K, editors. modern perspective. Dialogues Clin Neurosci 17:43–49. Psychiatry The State of the Art. New York: Springer Science 1 58. Lynall M-E, Bassett DS, Kerwin R, McKenna PJ, Kitzbichler M, Business Media, 59–64. Muller U, Bullmore E (2010): Functional connectivity and brain 31. American Psychiatric Association (2000): Diagnostical and Statistical networks in schizophrenia. J Neurosci 30:9477–9487. Manual of Mental Disorders (4th Ed, Text Rev). Washington, DC: 59. Fornito A, Zalesky A, Pantelis C, Bullmore ET (2012): Schizophrenia, American Psychiatric Association. neuroimaging and connectomics. Neuroimage 62:2296–2314. 32. von Economo C, Koskinas G (1925): Die Cytoarchitektonik der 60. Collin G, Hulshoff Pol HE, Haijma SV, Cahn W, Kahn RS, van den Hirnrinde des Erwachsenen Menschen. Berlin, Germany: Springer. Heuvel MP (2011): Impaired cerebellar functional connectivity in 33. Scholtens LH, Reus MA De, Heuvel MP, Van Den (2015): Linking schizophrenia patients and their healthy siblings. Front Psychiatry contemporary high resolution magnetic resonance imaging to the 2:73. von Economo legacy: A study on the comparison of MRI cortical 61. Van den Heuvel MP, Sporns O (2013): An anatomical substrate for thickness and histological measurements of cortical structure. Hum integration among functional networks in human cortex. J Neurosci Brain Mapp 36:3038–3046. 33:14489–14500. ̈ 34. Hippius H, Muller N (2008): The work of Emil Kraepelin and his 62. Honey CJ, Sporns O, Cammoun L, Gigandet X, Thiran JP, Meuli R, ̈ research group in Munchen. Eur Arch Psychiatry Clin Neurosci Hagmann P (2009): Predicting human resting-state functional con- – 258:3 11. nectivity from structural connectivity. Proc Natl Acad Sci U S A 106: ̈ 35. Nissl F (1904): Histologische und histopathologische Arbeiten uber 2035–2040. die Grosshirnrinde, vol 1. Jena, Germany: Gustav Fischer. 63. Honey CJ, Thivierge JP, Sporns O (2010): Can structure predict 36. Alzheimer A (1907): Über eine eigenartige Erkrankung der Hirnrinde. function in the human brain? Neuroimage 52:766–776. – Allg Zschr Psychiatr Psych Gerichtl Med 64:146 148. 64. Greicius MD, Supekar K, Menon V, Dougherty RF (2009): Resting- 37. Alzheimer A (1906): Über einen eigenartigen schweren Erkrankung- state functional connectivity reflects structural connectivity in the β sproze der Hirnrincle. Neurol Cent 25:1134. default mode network. Cereb Cortex 19:72–78. ’ 38. Hippius H, Neundörfer G (2003): The discovery of Alzheimer s 65. van den Heuvel MP, Mandl RCW, Kahn RS, Hulshoff Pol HE (2009): – disease. Dialogues Clin Neurosci 5:101 108. Functionally linked resting-state networks reflect the underlying 39. Kraepelin E (1913): Psychiatry, 8th ed. Leipzig, Germany: Barth. structural connectivity architecture of the human brain. Hum Brain 40. Kraepelin E (1919): Dementia-Praecox and Paraphrenia. New York: Mapp 30:3127–3141. Huntington. 66. Kleist K (1934): Kriegsverletzungen des Gehirns in ihrer Bedeutung 41. Mott F (1920): Studies in the Pathology of Dementia Praecox. Proc R für die Hirnlokalisation und Hirnpathologie. Leipzig, Germany: Barth. Soc Med 13:25–63. 67. Nieuwenhuys R (2013): The myeloarchitectonic studies on the 42. Conn J (1934): An examination of the clinico-pathological evidence human cerebral cortex of the Vogt-Vogt school, and their signifi- offered for the concept of dementia praecox as a specific disease cance for the interpretation of functional neuroimaging data. Brain entity. Am J Psychiatry 90:1039–1082. Struct Funct 218:303–352. 43. Glantz L, Lewis D (2000): Decreased dendritic spine density on 68. Kleist K (1934): Der Bau- und Funktionsplan der Großhirnrinde. prefrontal cortical pyramidal neurons in schizophrenia. Arch Gen Gehirnpathologische und lokalisatorische Ergebnisse. 10 Mitteilung. Psychiatry 57:65–73. – 44. Glausier JR, Lewis DA (2013): Dendritic spine pathology in schizo- Nervenarzt 7:329 334. 69. Ungvari G (1993): The Wernicke-Kleist-Leonhard school of psychia- phrenia. Neuroscience 251:90–107. – 45. van den Heuvel MP, Scholtens LH, de Reus MA, Kahn RS (2015): try. Biol Psychiatry 34:749 752. – Associated microscale spine density and macroscale connectivity 70. Neumärker K-J, Bartsch AJ (2003): Karl Kleist (1879-1960) a – disruptions in schizophrenia [published online ahead of print October pioneer of neuropsychiatry. Hist Psychiatry 14:411 458. 3]. Biol Psychiatry 71. Stephan KE, Friston KJ, Frith CD (2009): Dysconnection in schizo- 46. Ross C (2014): Dissociation in classical texts on schizophrenia. phrenia: From abnormal synaptic plasticity to failures of self- – Psychosis 2439:1–13. monitoring. Schizophr Bull 35:509 527. 47. Van den Heuvel MP, Sporns O (2011): Rich-club organization of the 72. Van den Heuvel MP, Kahn RS (2011): Abnormal brain wiring as a human connectome. J Neurosci 31:15775–15786. pathogenetic mechanism in schizophrenia. Biol Psychiatry 70: – 48. Van den Heuvel MP, Kahn RS, Goñi J, Sporns O (2012): High-cost, 1107 1108. et al high-capacity backbone for global brain communication. Proc Natl 73. Fornito A, Harrison BJ, Goodby E, Dean A, Ooi C, Nathan PJ, . Acad Sci U S A 109:11372–11377. (2013): Functional dysconnectivity of corticostriatal circuitry as a risk 49. Sporns O (2013): The human connectome: Origins and challenges. phenotype for psychosis. JAMA Psychiatry 70:1143–1151. Neuroimage 80:53–61. 74. Turing A (1936): On computable numbers, with an application to the 50. Van den Heuvel MP, Sporns O, Collin G, Scheewe T, Mandl RCW, Entscheidungsproblem. Proc London Math Soc 42:230–265. Cahn W, et al. (2013): Abnormal rich club organization and functional 75. Copeland B, Proudfoot D (2011): Alan Turing, father of the modern brain dynamics in schizophrenia. JAMA Psychiatry 70:783–792. computer. The Rutherford Journal 4. 51. Collin G, Kahn R, de Reus M, Cahn W, van den Heuvel M (2014): 76. Wiener N (1948): Cybernetics or Control and Communication in the Impaired rich club connectivity in unaffected siblings of schizophre- Animal and the Machine. Cambridge, MA: MIT Press. nia patients. Schizophr Bull 40:438–448. 77. Sporns O (2010): Brain network disease. Networks of the brain. 52. Griffa A, Baumann P, Ferrari C, Do K, Conus P, Thiran J, Hagmann P Cambridge, MA: MIT Press, 207–208. (2015): Characterizing the dysconnectivity syndrome of schizophre- 78. Laborit H, Huguenard P, Alluame R (1952): Un noveau stabilisateur nia with diffusion spectrum imaging. Hum Brain Mapp 366:354–366. végétatif. La Press Médicale 60:206–208. 53. Lynall M, Bassett DS, Kerwin R, Mckenna PJ, Müller U, Bullmore E 79. Ban TA (2007): Fifty years chlorpromazine: A historical perspective. (2011): Functional connectivity and brain networks in schizophrenia. Neuropsychiatr Dis Treat 3:495–500. J Neurosci 30:9477–9487. 80. Hamon J, Paraire J, Velluz J (1952): Remarques sur l’action du 4560 54. Rubinov M, Bullmore E (2013): Schizophrenia and abnormal brain RP sur l’agitation maniaque. Ann Med Psychol (Paris) 110:403–407. network hubs. Dialogues Clin Neurosci 15:339–349. 81. Carpenter WT, Davis JM (2012): Another view of the history of 55. Eysenck H, Barrett P (1993): The nature of schizotypy. Psychol Rep antipsychotic drug discovery and development. Mol Psychiatry 17: 73:59–63. 1168–1173. 56. Heckers S (2011): Bleuler and the neurobiology of schizophrenia. 82. Mesulam MM (2015): Fifty years of disconnexion syndromes and the Schizophr Bull 37:1131–1135. Geschwind legacy. Brain 138:2791–2799.

8 Biological Psychiatry: Cognitive Neuroscience and Neuroimaging ]]] 2016; ]:]]]–]]] www.sobp.org/BPCNNI Biological Psychiatry: The History of Connectomics in Schizophrenia CNNI

83. Geschwind N (1965): Disconnection syndromes in animals and man. 105. Johansen-Berg H, Rushworth MFS, Bogdanovic MD, Kischka U, Part I. Brain 88:237–294. Wimalaratna S, Matthews PM (2002): The role of ipsilateral premotor 84. Geschwind N (1965): Disconnexion syndromes in animals and man. cortex in hand movement after stroke. Proc Natl Acad Sci U S A 99: Part II. Brain 88:585–644. 14518–14523. 85. Catani M (2005): The rises and falls of disconnection syndromes. 106. Riecker A, Gröschel K, Ackermann H, Schnaudigel S, Kassubek J, Brain 128:2224–2239. Kastrup A (2010): The role of the unaffected hemisphere in motor 86. Wernicke C (1994): The aphasia symptom-complex: A psychological recovery after stroke. Hum Brain Mapp 31:1017–1029. study on an anbatomical basis (1875). In: Eling P, editor. Reader in 107. Stephan KE, Baldeweg T, Friston KJ (2006): Synaptic plasticity and the History of Aphasia, vol. 4. Amsterdam: John Benjamins, 69–89. dysconnection in schizophrenia. Biol Psychiatry 59:929–939. ̈ 87. Lichtheim L (1885): Uber Aphasie. Aus der Med Klin Bern Dtsch Arch 108. Stephan KE, Iglesias S, Heinzle J, Diaconescu AO (2015): Transla- ̈ ̈ fur Klin Med. Munchen, Germany: Bergmann, 204–628. tional perspectives for computational neuroimaging. Neuron 87: 88. Flechsig P (1901): Developmental (myelogenetic) localisation of the 716–732. cerebral cortex in the human subject. Lancet 2:1027. 109. Friston KJ (1998): The disconnection hypothesis. Schizophr Res 30: 89. Liepman H (1900): as Krankheitsbild der Apraxie (motorische Asym- 115–125. bolie) auf Grund eines Falles von einseitiger Apraxie. Monatssch 110. Schizophrenia Working Group of the Psychiatric Genomics Con- – – – Psychia Neurol 8:15 44,102 132, 182 197. sortium (2014): Biological insights from 108 schizophrenia- 90. Weinberger DR, Berman KF, Suddath R, Fuller Torrey E (1992): associated genetic loci. Nature 511:421–427. Evidence of dysfunction of a prefrontal-limbic network in schizo- 111. Kubicki M, McCarley R, Westin C-F, Park H-J, Maier S, Kikinis R, phrenia: A magnetic resonance imaging and regional cerebral blood et al. (2007): A review of diffusion tensor imaging studies in fl ow study of discordant monozygotic twins. Am J Psychiatry 149: schizophrenia. J Psychiatr Res 41:15–30. – 890 897. 112. Fitzsimmons J, Kubicki M, Shenton ME (2013): Review of functional ’ 91. Andreasen NC, O Leary DS, Cizadlo T, Arndt S, Rezai K, Ponto LL, and anatomical brain connectivity findings in schizophrenia. Curr et al . (1996): Schizophrenia and cognitive dysmetria: A positron- Opin Psychiatry 26:172–187. emission tomography study of dysfunctional prefrontal-thalamic- 113. Kubicki M, Shenton ME (2014): Diffusion tensor imaging findings and – cerebellar circuitry. Proc Natl Acad Sci U S A 93:9985 9990. their implications in schizophrenia. Curr Opin Psychiatry 27:179–184. 92. Fristen KJ, Frith CD, Fletcher P, Liddle PF, Frackowiak RSJ (1996): 114. Wheeler AL, Voineskos AN (2014): A review of structural neuro- Functional topography: Multidimensional scaling and functional imaging in schizophrenia: From connectivity to connectomics. Front connectivity in the brain. Cereb Cortex 6:156–164. Hum Neurosci 8:653. 93. Mallet L, Mazoyer B, Martinot J (1998): Functional connectivity in 115. Sporns O (2011): The human connectome: A complex network. Ann depressive, obsessive-compulsive, and schizophrenic disorders: An N Y Acad Sci 1224:109–125. explorative correlational analysis of regional cerebral metabolism. 116. Li Y, Liu Y, Li J, Qin W, Li K, Yu C, Jiang T (2009): Brain anatomical Psychiatry Res 82:83–93. network and intelligence. PLoS Comput Biol 5:e1000395. 94. Saito N, Kuginuki T, Yagyu T, Kinoshita T, Koenig T, Pascual-Marqui 117. Van den Heuvel MP, Stam CJ, Kahn RS, Hulshoff Pol HE (2009): RD, et al. (1998): Global, regional, and local measures of complexity Efficiency of functional brain networks and intellectual performance. of multichannel electroencephalography in acute, neuroleptic-naïve, J Neurosci 29:7619–7624. first-break schizophrenics. Biol Psychiatry 43:794–802. 118. Baggio H, Segura B, Junque C, De Reus M, Sala-Llonch R, Van den 95. Breier A, Buchanan R, Elkashef A, Munson R, Kirkpatrick B, Gellad F Heuvel M (2015): Rich club organization and cognitive performance (1992): Brain morphology and schizophrenia. A magnetic resonance in healthy older participants. J Cogn Neurosci 27:1801–1810. imaging study of limbic, prefrontal cortex, and caudate structures. 119. Bassett DS, Bullmore ET, Meyer-Lindenberg A, Apud JA, Weinberger Arch Gen Psychiatry 49:921–926. DR, Coppola R (2009): Cognitive fitness of cost-efficient brain 96. Buchanan R, Vladar K, Barta P, Pearlson G (1998): Structural functional networks. Proc Natl Acad Sci U S A 106:11747–11752. evaluation of the prefrontal cortex in schizophrenia. Am J Psychiatry 120. Cole MW, Yarkoni T, Repovs G, Anticevic A, Braver TS (2012): Global 155:1049–1055. connectivity of prefrontal cortex predicts cognitive control and 97. Lim KO, Adalsteinsson E, Spielman D, Sullivan EV, Rosenbloom MJ, – Pfefferbaum A (1998): Proton magnetic resonance spectroscopic intelligence. J Neurosci 32:8988 8999. imaging of cortical gray and white matter in schizophrenia. Arch Gen 121. Adelstein JS, Shehzad Z, Mennes M, Deyoung CG, Zuo X-N, Kelly C, et al fl ’ Psychiatry 55:346–352. . (2011): Personality is re ected in the brain s intrinsic functional 98. Buchsbaum MS, Tang CY, Peled S, Gudbjartsson H, Lu D, Hazlett architecture. PLoS One 6:e27633. et al EA, et al. (1998): MRI white matter diffusion anisotropy and PET 122. Gao Q, Xu Q, Duan X, Liao W, Ding J, Zhang Z, . (2013): metabolic rate in schizophrenia. Neuroreport 9:425–430. Extraversion and neuroticism relate to topological properties of 99. Lim KO, Hedehus M, Moseley M, de Crespigny A, Sullivan EV, resting-state brain networks. Front Hum Neurosci 7:257. Pfefferbaum A (1999): Compromised white matter tract integrity in 123. Ryman SG, van den Heuvel MP, Yeo RA, Caprihan A, Carrasco J, et al schizophrenia inferred from diffusion tensor imaging. Arch Gen Vakhtin AA, . (2014): Sex differences in the relationship between – Psychiatry 56:367–374. white matter connectivity and creativity. Neuroimage 101:380 389. 100. Harrison PJ (1999): The neuropathology of schizophrenia. A critical 124. Fornito A, Zalesky A, Breakspear M (2015): The connectomics of review of the data and their interpretation. Brain 122:593–624. brain disorders. Nat Rev Neurosci 16:159–172. 101. Sweet R, Henteleff R, Zhang W, Sampson A, Lewis D (2009): 125. van den Heuvel MP, Hulshoff Pol HE (2010): Exploring the brain Reduced dendritic spine density in auditory cortex of subjects with network: A review on resting-state fMRI functional connectivity. Eur schizophrenia. Neuropsychopharmacology 34:374–389. Neuropsychopharmacol 20:519–534. 102. Uranova NA, Vostrikov VM, Vikhreva OV, Zimina IS, Kolomeets NS, 126. Crossley NA, Mechelli A, Scott J, Carletti F, Fox PT, McGuire P, Orlovskaya DD (2007): The role of oligodendrocyte pathology in Bullmore ET (2014): The hubs of the human connectome are schizophrenia. Int J Neuropsychopharmacol 10:537–545. generally implicated in the anatomy of brain disorders. Brain 137: 103. Uranova N, Vikhreva O, Rachmanova V, Orlovskaya D (2011): Ultra- 2382–2395. structural alterations of myelinated fibers and oligodendrocytes in 127. Stam CJ (2014): Modern network science of neurological disorders. the prefrontal cortex in schizophrenia: A postmortem morphometric Nat Rev Neurosci 15:683–695. study. Schizophr Res Treatment 2011:325789. 128. Collin G, van den Heuvel MP, Abramovic L, Vreeker A, de Reus MA, 104. Pettersson-Yeo W, Allen P, Benetti S, McGuire P, Mechelli A (2011): van Haren NE, et al. (2015): Brain network analysis reveals affected Dysconnectivity in schizophrenia: Where are we now? Neurosci connectome structure in bipolar I disorder. Hum Brain Mapp 37: Biobehav Rev 35:1110–1124. 122–134.

Biological Psychiatry: Cognitive Neuroscience and Neuroimaging ]]] 2016; ]:]]]–]]] www.sobp.org/BPCNNI 9 Biological Psychiatry: CNNI The History of Connectomics in Schizophrenia

129. Daianu M, Jahanshad N, Nir TM, Jack CR Jr, Weiner MW, Bernstein tractography and tract-tracing measures of connectivity strength in MA, Thompson PM (2015): Rich club analysis in the Alzheimer’s rhesus macaque connectome. Hum Brain Mapp 36:3064–3075. disease connectome reveals a relatively undisturbed structural core 140. van den Heuvel MP, Scholtens LH, Feldman Barrett L, Hilgetag CC, network. Hum Brain Mapp 36:3087–3103. de Reus MA (2015): Bridging cytoarchitectonics and connectomics 130. Dima D, Dietrich DE, Dillo W, Emrich HM (2010): Impaired top-down in human cerebral cortex. J Neurosci 35:13943–13948. processes in schizophrenia: A DCM study of ERPs. Neuroimage 52: 141. Scholtens LH, Schmidt R, de Reus MA, van den Heuvel MP (2014): 824–832. Linking macroscale graph analytical organization to microscale 131. Dima D, Roiser JP, Dietrich DE, Bonnemann C, Lanfermann H, neuroarchitectonics in the macaque connectome. J Neurosci 34: Emrich HM, Dillo W (2009): Understanding why patients with 12192–12205. schizophrenia do not perceive the hollow-mask illusion using 142. Collin G, de Nijs J, Hulshoff Pol HE, Cahn W, van den Heuvel MP dynamic causal modelling. Neuroimage 46:1180–1186. (2015): Connectome organization is related to longitudinal changes 132. Deserno L, Sterzer P, Wu T, Heinz A, Schlagenhauf F (2012): in general functioning, symptoms and IQ in chronic schizophrenia Reduced prefrontal-parietal effective connectivity and working mem- [published online ahead of print April 2]. Schizophr Res. ory deﬁcits in schizophrenia. J Neurosci 32:12–20. 143. Irimia A, Wang B, Aylward SR, Prastawa MW, Pace DF, Gerig G, 133. Vertes PE, Alexander-Bloch AF, Gogtay N, Giedd JN, Rapoport JL, et al. (2012): Neuroimaging of structural pathology and connectom- Bullmore ET (2012): Simple models of human brain functional net- ics in traumatic brain injury: Toward personalized outcome predic- works. Proc Natl Acad Sci U S A 109:5868–5873. tion. Neuroimage Clin 1:1–17. 134. Cabral J, Hugues E, Kringelbach ML, Deco G (2012): Modeling the 144. van Essen D, Barch D (2015): The human connectome in health and outcome of structural disconnection on resting-state functional psychopathology. World Psychiatry 14:154–157. connectivity. Neuroimage 62:1342–1353. 145. Meynert T (1892): Neue Studien über die Associations-Bündel des 135. Breakspear M, Jirsa V, Deco G (2010): Computational models of the Hirnmantels. Indic Austrian Acad Sci Math-Natural Sci Cl 101: brain: From structure to function. Neuroimage 52:727–730. 361–380. 136. Deco G, Senden M, Jirsa V (2012): How anatomy shapes dynamics: 146. Wernicke C (1874): Der Aphasische Symptomencomplex. Breslau, A semi-analytical study of the brain at rest by a simple spin model. Germany: Max Cohn and Weigert. In: Cohen RS, Wartofsky MW, Front Comput Neurosci 6:68. editors. Boston Studies in the Philosophy of Science, vol. IV). 137. Woolrich MW, Stephan KE (2013): Biophysical network models and Dordrecht, The Netherlands: Reidel (German, trans 1969). the human connectome. Neuroimage 80:330–338. 147. Graves RE (1997): The legacy of the Wernicke-Lichtheim model. 138. Thompson PM, Ge T, Glahn DC, Jahanshad N, Nichols TE (2013): J Hist Neurosci 6:3–20. Genetics of the connectome. Neuroimage 80:475–488. 148. Catani M, Mesulam M (2008): The arcuate fasciculus and the 139. van den Heuvel MP, de Reus MA, Feldman Barrett L, Scholtens LH, disconnection theme in language and aphasia: History and current Coopmans FM, Schmidt R, et al. (2015): Comparison of diffusion state. Cortex 44:953–961.

10 Biological Psychiatry: Cognitive Neuroscience and Neuroimaging ]]] 2016; ]:]]]–]]] www.sobp.org/BPCNNI