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 develop- ments 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 dis- ruptions 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