Connectomics and Psychopathology: A Budding Grove of New Thinking, Research

Neuroscience is moving toward a fairly unified explanation of psychopathology at the level of circuits and systems. The following articles/reviews on connectomics redirect our attention to mental illness as a disorder of connectivity. I’ve also embedded a foundational talk by Olaf Sporns, author of Networks of the Brain (MIT, 2010; reviewed by Terrence Sejnowski for American Scientist Online).

Behrans, T. E. J., & Sporns, O. (2012). Human connectomics. Current Opinion in Neurobiology, 22(1), 144–153. http://dx.doi.org/10.1016/j.conb.2011.08.005

Recent advances in non-invasive neuroimaging have enabled the measurement of connections between distant regions in the living human brain, thus opening up a new field of research: Human connectomics. Different imaging modalities allow the mapping of structural connections (axonal fibre tracts) as well as functional connections (correlations in time series), and individual variations in these connections may be related to individual variations in behaviour and cognition. Connectivity analysis has already led to a number of new insights about brain organization. For example, segregated brain regions may be identified by their unique patterns of connectivity, structural and functional connectivity may be compared to elucidate how dynamic interactions arise from the anatomical substrate, and the architecture of large-scale networks connecting sets of brain regions may be analysed in detail. The combined analysis of structural and functional networks has begun to reveal components or modules with distinct patterns of connections that become engaged in different cognitive tasks. Collectively, advances in human connectomics open up the possibility of studying how brain connections mediate regional brain function and thence behaviour.

Buckholtz, J. W., & Meyer-Lindenberg, A. (2012). Psychopathology and the human connectome: Toward a transdiagnostic model of risk for mental illness [Review]. Neuron, 74(6), 990–1004. http://dx.doi.org/10.1016/j.neuron.2012.06.002

The panoply of cognitive, affective, motivational, and social functions that underpin everyday human experience requires precisely choreographed patterns of interaction between networked brain regions. Perhaps not surprisingly, diverse forms of psychopathology are characterized by breakdowns in these interregional relationships. Here, we discuss how functional brain imaging has provided insights into the nature of brain dysconnectivity in mental illness. Synthesizing work to date, we propose that genetic and environmental risk factors impinge upon systems-level circuits for several core dimensions of cognition, producing transdiagnostic symptoms. We argue that risk-associated disruption of these circuits mediates susceptibility to broad domains of psychopathology rather than discrete disorders.

Bullmore, E. T., & Sporns, O. (2012). The economy of brain network organization.  Nature Reviews Neuroscience, 13, 336–349. http://dx.doi.org/10.1038/nrn3214

The brain is expensive, incurring high material and metabolic costs for its size — relative to the size of the body — and many aspects of brain network organization can be mostly explained by a parsimonious drive to minimize these costs. However, brain networks or connectomes also have high topological efficiency, robustness, modularity and a ‘rich club’ of connector hubs. Many of these and other advantageous topological properties will probably entail a wiring-cost premium. We propose that brain organization is shaped by an economic trade-off between minimizing costs and allowing the emergence of adaptively valuable topological patterns of anatomical or functional connectivity between multiple neuronal populations. This process of negotiating, and re-negotiating, trade-offs between wiring cost and topological value continues over long (decades) and short (millisecond) timescales as brain networks evolve, grow and adapt to changing cognitive demands. An economical analysis of neuropsychiatric disorders highlights the vulnerability of the more costly elements of brain networks to pathological attack or abnormal development.

Fornito, A., & Bullmore, E. T. (2012). Connectomic intermediate phenotypes for psychiatric disorders. Frontiers in Psychiatry, 3(32). http://dx.doi.org/10.3389/fpsyt.2012.00032

Psychiatric disorders are phenotypically heterogeneous entities with a complex genetic basis. To mitigate this complexity, many investigators study so-called intermediate phenotypes (IPs) that putatively provide a more direct index of the physiological effects of candidate genetic risk variants than overt psychiatric syndromes. Magnetic resonance imaging (MRI) is a particularly popular technique for measuring such phenotypes because it allows interrogation of diverse aspects of brain structure and function in vivo. Much of this work however, has focused on relatively simple measures that quantify variations in the physiology or tissue integrity of specific brain regions in isolation, contradicting an emerging consensus that most major psychiatric disorders do not arise from isolated dysfunction in one or a few brain regions, but rather from disturbed interactions within and between distributed neural circuits; i.e., they are disorders of brain connectivity. The recent proliferation of new MRI techniques for comprehensively mapping the entire connectivity architecture of the brain, termed the human connectome, has provided a rich repertoire of tools for understanding how genetic variants implicated in mental disorder impact distinct neural circuits. In this article, we review research using these connectomic techniques to understand how genetic variation influences the connectivity and topology of human brain networks. We highlight recent evidence from twin and imaging genetics studies suggesting that the penetrance of candidate risk variants for mental illness, such as those in SLC6A4, MAOA,ZNF804A, and APOE, may be higher for IPs characterized at the level of distributed neural systems than at the level of spatially localized brain regions. The findings indicate that imaging connectomics provides a powerful framework for understanding how genetic risk for psychiatric disease is expressed through altered structure and function of the human connectome.

Fornito, A., Zalesky, A., Pantelis, C., & Bullmore, E. T. (2012). Schizophrenia, neuroimaging and connectomics [Review]. NeuroImage. Advance online publication. http://dx.doi.org/10.1016/j.neuroimage.2011.12.090

Schizophrenia is frequently characterized as a disorder of brain connectivity. Neuroimaging has played a central role in supporting this view, with nearly two decades of research providing abundant evidence of structural and functional connectivity abnormalities in the disorder. In recent years, our understanding of how schizophrenia affects brain networks has been greatly advanced by attempts to map the complete set of inter-regional interactions comprising the brain’s intricate web of connectivity; i.e., the human connectome. Imaging connectomics refers to the use of neuroimaging techniques to generate these maps which, combined with the application of graph theoretic methods, has enabled relatively comprehensive mapping of brain network connectivity and topology in unprecedented detail. Here, we review the application of these techniques to the study of schizophrenia, focusing principally on magnetic resonance imaging (MRI) research, while drawing attention to key methodological issues in the field. The published findings suggest that schizophrenia is associated with a widespread and possibly context-independent functional connectivity deficit, upon which are superimposed more circumscribed, context-dependent alterations associated with transient states of hyper- and/or hypo-connectivity. In some cases, these changes in inter-regional functional coupling dynamics can be related to measures of intra-regional dysfunction. Topological disturbances of functional brain networks in schizophrenia point to reduced local network connectivity and modular structure, as well as increased global integration and network robustness. Some, but not all, of these functional abnormalities appear to have an anatomical basis, though the relationship between the two is complex. By comprehensively mapping connectomic disturbances in patients with schizophrenia across the entire brain, this work has provided important insights into the highly distributed character of neural abnormalities in the disorder, and the potential functional consequences that these disturbances entail.

Hagmann, P., Grant, P., & Fair, D. (June, 2012). MR connectomics: A conceptual framework for studying the developing brain [Review]. Frontiers in Systems Neuroscience. http://dx.doi.org/10.3389/fnsys.2012.00043

The combination of advanced neuroimaging techniques and major developments in complex network science, have given birth to a new framework for studying the brain: “connectomics.” This framework provides the ability to describe and study the brain as a dynamic network and to explore how the coordination and integration of information processing may occur. In recent years this framework has been used to investigate the developing brain and has shed light on many dynamic changes occurring from infancy through adulthood. The aim of this article is to review this work and to discuss what we have learned from it. We will also use this body of work to highlight key technical aspects that are necessary in general for successful connectome analysis using today’s advanced neuroimaging techniques. We look to identify current limitations of such approaches, what can be improved, and how these points generalize to other topics in connectome research.

Power, J. D., Cohen, A. L., Nelson, S. M., Wig, G. S., Barnes, K. A., Church, J. A., . . . Petersen, S. E. (2011). Functional network organization of the human brain. Neuron, 72, 665–678. http://dx.doi.org/10.1016/j.neuron.2011.09.006

Real-world complex systems may be mathematically modeled as graphs, revealing properties of the system. Here we study graphs of functional brain organization in healthy adults using resting state functional connectivity MRI. We propose two novel brain-wide graphs, one of 264 putative functional areas, the other a modification of voxelwise networks that eliminates potentially artificial short-distance relationships. These graphs contain many subgraphs in good agreement with known functional brain systems. Other subgraphs lack established functional identities; we suggest possible functional characteristics for these subgraphs. Further, graph measures of the areal network indicate that the default mode subgraph shares network properties with sensory and motor subgraphs: it is internally integrated but isolated from other subgraphs, much like a “processing” system. The modified voxelwise graph also reveals spatial motifs in the patterning of systems across the cortex.

Tost, H., Bilek, E., & Meyer-Lindenberg, A. (2011). Brain connectivity in psychiatric imaging genetics. NeuroImage. Advance online publication. http://dx.doi.org/10.1016/j.neuroimage.2011.11.007

In the past decade, imaging genetics has evolved into a highly successful neuroimaging discipline with a variety of sophisticated research tools. To date, several neural systems mechanisms have been identified that mediate genetic risk for mental disorders linked to common candidate and genome-wide-supported variants. In particular, the examination of intermediate connectivity phenotypes has recently gained increasing popularity. This paper gives an overview of the scientific methods and evidence that link indices of neural network organization to the genetic susceptibility for mental illness with a focus on the effects of candidate genes and genome-wide supported risk variants on brain structure and function.

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About Constance A. Cummings

Constance A. Cummings, PhD, is Project Director of the non-profit Foundation for Psychocultural Research, which supports and advances interdisciplinary research and scholarship at the intersection of brain, mind, culture, and mental health and illness. She is co-editor (with Carol Worthman, Paul Plotsky, and Dan Schechter) of Formative Experiences: The Interaction of Caregiving, Culture, and Developmental Psychobiology (Cambridge University Press, 2010) and (with Laurence Kirmayer and Rob Lemelson) the forthcoming Re-Visioning Psychiatry: Cultural Phenomenology, Critical Neuroscience, and Global Mental Health (Cambridge, 2015). She received her doctorate in theoretical linguistics from New York University.

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