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Abnormal Brain Wiring as a Pathogenetic Mechanism in Schizophrenia
Abnormal Brain Wiring as a Pathogenetic Mechanism in Schizophrenia Martijn P. van den Heuvel and René S. Kahn ur brain is a network. On a macroscopic level, hundreds of brain regions, each having their own task or function, interact through thousands of structural connections, continuously processing, sharing, and integrating information. Driven by advances in neuroimaging techniques and mathematics, it has now become increasingly feasible to examine large scale brain connectivity, both structurally and functionally (1). Structural connectivity refers to the physical connections between brain regions, such as white matter pathways; functional connectivity refers to the level of statistical dependence between activation patterns of brain regions, often believed to reflect, to some extent, large-scale neuronal communication. High levels of efficient functional and structural brain connectivity are known to be crucial for healthy performance of the brain (2). Conversely, one may expect abnormalities in connectivity of the brain to relate to psychiatric illnesses, such as schizophrenia. It has indeed been hypothesized for more than a century that schizophrenia is related to abnormal brain connectivity. Wernicke suggested that psychotic symptoms may result from structural abnormalities of association tracts in the brain. What’s more, Bleuler defined the illness on the fragmented (or split) thinking observed in people with the disorder (for a review, see [3]). The rise of modern neuroimaging techniques has revived the hypothesis that schizophrenia is a result of abnormal brain connectivity. Consequently, a growing number of studies has examined brain connectivity in schizophrenia, finding it to be abnormal. Diffusion imaging studies have shown white matter disconnectivity on a macroscopic level, reporting reduced integrity of key frontal-temporal white matter connections (for a review, see review [4]). Furthermore, functional connectivity studies have reported abnormal functional coupling between frontal, parietal, and temporal brain areas in patients (5,6). However, it remains unknown which connections are specifically affected and how this abnormal connectivity is linked to different aspects of the disease. The paper by Hinkley et al. (7) in this issue of Biological Psychiatry is one of the first studies to show how symptoms are related to disrupted functional connectivity of the brain in schizophrenia. Using functional connectivity analysis of source-space reconstructions of resting-state magnetoencephalographic sensor recordings of 30 patients with schizophrenia and 15 healthy controls, Hinkley et al. (7) examined differences in functional coupling between cortical regions in patients. A level of global connectivity was computed for each cortical region as the total sum of connectivity to all other regions, interpreted by the authors as a measure of how well a particular region is connected to the rest of the brain. The authors report reduced connectivity of left prefrontal cortex and right superior temporal cortex in patients, together with an increase in connectivity of the left extrastriate visual cortex and right
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From the Department of Psychiatry, University Medical Center Utrecht, Rudolf Magnus Institute of Neuroscience, Utrecht, The Netherlands. Address correspondence to Martijn van den Heuvel, Ph.D., Department of Psychiatry, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, Heidelberglaan 100, 3508 GA Utrecht, P.O. Box 85500, Utrecht, The Netherlands; E-mail: [email protected]. Received Oct 18, 2011; accepted Oct 19, 2011.
0006-3223/$36.00 doi:10.1016/j.biopsych.2011.10.020
inferior prefrontal cortex. Furthermore, functional connectivity of the left inferior parietal and left insular cortex was found to be negatively correlated with severity of psychotic symptoms. As suggested by the authors, this correlation might reflect a diminished functional role of these regions in the language network, leading toward abnormal auditory perceptual experiences. Second, lower levels of connectivity of the left prefrontal cortex was found to be significantly correlated with negative symptoms, suggesting that a reduced functional coupling of prefrontal regions is related to more severe negative symptoms. Third, depressive symptoms were found to be related to lower levels of global connectivity of the anterior cingulate cortex. Finally, severity of cognitive features (including attention and disorientation) was associated with lower levels of functional coupling of the right dorsolateral prefrontal cortex, a region well known to play a key role in working memory, attention, and general cognitive processes. The paper by Hinkley et al. (7) extends recent findings linking changes in brain connectivity to symptoms in schizophrenia. A resting-state connectivity study, using functional magnetic resonance imaging rather than magnetoencephalography recordings to measure functional connectivity, showed that local reductions in connectivity of the prefrontal cortex in patients were associated with cognitive disruption, whereas increased global connectivity was found to be related to the severity of disorganization and reality distortion (8). In addition, increased levels of functional connectivity between frontal and parietal brain regions were found to be robustly predictive of better cognitive performance in patients and their siblings as well as lower levels of disorganization (6). Hinkley et al. (7) examined how symptoms are related to abnormal connectivity between specific brain regions. In addition to this approach, others have adopted the view that schizophrenia may not be related to abnormalities of specific brain regions but rather be the result of an underlying aberrant organization of the brain network as a whole. Such network studies are motivated by the concept that brain function, and by inference dysfunction of the brain, may not solely be related to the properties of particular brain regions or specific connections but rather emerges from the interactions of the complete network, the so-called brain’s connectome (1). The human connectome is a detailed map of all neural connections of our brain, and the emerging field of connectomics attempts to create and study this comprehensive map of neural circuits on both the microscopic and a whole-brain macroscopic level (1). Landmark studies in this emerging field have shown that the connections of the human brain are not random but rather are organized according to a highly efficient topology (9). The brain’s network combines local information processing with efficient global integration of information between distant parts of the network (9,10), an organization shown to be critical for healthy brain functioning (2). It has been suggested that schizophrenia may be related to an abnormal wiring pattern of the brain, particularly a reduced level of global integration across the network (11). Three studies have revealed evidence for connectome abnormalities in schizophrenia, observing reduced wiring and diminished global efficiency in patients (5,11,12). Consistent with the findings of Hinkley et al. (7), these results suggest an abnormal organization of the brain’s network in patients, with a reduced central hub role of BIOL PSYCHIATRY 2011;70:1107–1108 © 2011 Society of Biological Psychiatry
1108 BIOL PSYCHIATRY 2011;70:1107–1108 frontal regions (5,11). Brain hubs are regions with an above average number of connections that take a central position in the network; they have been suggested to be a focal point for large-scale communication in the human brain (9,10). In this context it has been hypothesized that diminished functioning of key brain hubs in schizophrenia may lead to inefficient information integration between the different regions of the brain (5,11). So far, however, these network studies have not been able to find a clear association between aberrant brain network topology and cognitive symptoms in schizophrenia (5,11,12), as reported in the study by Hinkley et al. (7). Be that as it may, our current knowledge about the brain’s network is just the proverbial tip of the iceberg. Emerging new technology will enable the creation of more detailed connectivity maps and drive discoveries on the fundamental organization of the human connectome and its critical role in the (dys)functioning of the brain. We strongly believe that studying the neural circuits of the brain will ultimately elucidate how the healthy human brain works and consequently help unravel the pathology of many, if not all, psychiatric disorders. A pivotal question remains: where does this abnormal brain connectivity originate? One hypothesis is that abnormal brain wiring may result from aberrant maturation of the connectome during brain development. Currently our knowledge of healthy brain development is limited, certainly regarding the formation of brain connections. Understanding changes in the brain’s connections will be essential in explaining the underlying brain pathology in schizophrenia and possibly that of many other psychiatric disorders. The development of the brain’s network may reflect a shift from a local to a more global organization, in which the level of information integration is optimized between the distant parts of the brain (13). However, many questions about healthy brain development remain, such as the following: what underlying mechanism enforces this shift from a local-to-global orientation, which pathways are involved, what is the role of brain hubs in this process, and in particular how are these processes linked to the maturation of human cognition? Large-scale population imaging, following large number of subjects in a longitudinal setting, provides an opportunity to find answers to these questions. Such studies will provide fundamental knowledge on normal brain maturation, information that will be crucial to generate new ways for early detection of abnormal developmental trajectories leading toward psychiatric illnesses (13).
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Commentary In summary, the study by Hinkley et al. (7) presents a novel finding on one of the missing links in schizophrenia research, associating as they do abnormal brain connectivity with specific symptoms of the disease. Their study heralds an important new field of study: examining how abnormal brain wiring is related to the development of psychiatric diseases. The authors reported no biomedical financial interests or potential conflicts of interest. 1. Bullmore E, Sporns O (2009): Complex brain networks: graph theoretical analysis of structural and functional systems. Nat Rev 10:186 –198. 2. van den Heuvel MP, Stam CJ, Kahn RS, Hulshoff Pol HE (2009): Efficiency of functional brain networks and intellectual performance. J Neurosci 29:7619 –7624. 3. Stephan KE, Friston KJ, Frith CD (2009): Dysconnection in schizophrenia: from abnormal synaptic plasticity to failures of self-monitoring. Schizophr Bull 35:509 –527. 4. Ellison-Wright I, Bullmore E (2009): Meta-analysis of diffusion tensor imaging studies in schizophrenia. Schizophr Res 108:3–10. 5. Lynall ME, Bassett DS, Kerwin R, McKenna PJ, Kitzbichler M, Muller U, et al. (2010): Functional connectivity and brain networks in schizophrenia. J Neurosci 30:9477–9487. 6. Repovs G, Csernansky JG, Barch DM (2010): Brain network connectivity in individuals with schizophrenia and their siblings. Biol Psychiatry 69: 967–973. 7. Hinkley LBN, Vinogradov S, Guggisberg AG, Fisher M, Findlay AM, Nagarajan SS (2011): Clinical symptoms and alpha band resting-state functional connectivity imaging in patients with schizophrenia: implications for novel approaches to treatment. Biol Psychiatry 70:1134 –1142. 8. Cole MW, Anticevic A, Repovs G, Barch D (2011): Variable global dysconnectivity and individual differences in schizophrenia. Biol Psychiatry 70: 43–50. 9. Hagmann P, Cammoun L, Gigandet X, Meuli R, Honey CJ, Wedeen VJ, et al. (2008): Mapping the structural core of human cerebral cortex. PLoS Biol 6:e159. 10. van den Heuvel MP, Sporns O (2011): Rich-club organization of the human connectome. J Neurosci 31:15775–15786. 11. van den Heuvel MP, Mandl RC, Stam CJ, Kahn RS, Hulshoff Pol HE (2010): Aberrant frontal and temporal complex network structure in schizophrenia: a graph theoretical analysis. J Neurosci 30:15915–15926. 12. Zalesky A, Fornito A, Seal ML, Cocchi L, Westin CF, Bullmore ET, et al. (2011): Disrupted axonal fiber connectivity in schizophrenia. Biol Psychiatry 69:80 – 89. 13. Dosenbach NU, Nardos B, Cohen AL, Fair DA, Power JD, Church JA, et al. (2010): Prediction of individual brain maturity using fMRI. Science 329: 1358 –1361.
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From the Department of Psychiatry, University Medical Center Utrecht, Rudolf Magnus Institute of Neuroscience, Utrecht, The Netherlands. Address correspondence to Martijn van den Heuvel, Ph.D., Department of Psychiatry, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, Heidelberglaan 100, 3508 GA Utrecht, P.O. Box 85500, Utrecht, The Netherlands; E-mail: [email protected]. Received Oct 18, 2011; accepted Oct 19, 2011.
0006-3223/$36.00 doi:10.1016/j.biopsych.2011.10.020
inferior prefrontal cortex. Furthermore, functional connectivity of the left inferior parietal and left insular cortex was found to be negatively correlated with severity of psychotic symptoms. As suggested by the authors, this correlation might reflect a diminished functional role of these regions in the language network, leading toward abnormal auditory perceptual experiences. Second, lower levels of connectivity of the left prefrontal cortex was found to be significantly correlated with negative symptoms, suggesting that a reduced functional coupling of prefrontal regions is related to more severe negative symptoms. Third, depressive symptoms were found to be related to lower levels of global connectivity of the anterior cingulate cortex. Finally, severity of cognitive features (including attention and disorientation) was associated with lower levels of functional coupling of the right dorsolateral prefrontal cortex, a region well known to play a key role in working memory, attention, and general cognitive processes. The paper by Hinkley et al. (7) extends recent findings linking changes in brain connectivity to symptoms in schizophrenia. A resting-state connectivity study, using functional magnetic resonance imaging rather than magnetoencephalography recordings to measure functional connectivity, showed that local reductions in connectivity of the prefrontal cortex in patients were associated with cognitive disruption, whereas increased global connectivity was found to be related to the severity of disorganization and reality distortion (8). In addition, increased levels of functional connectivity between frontal and parietal brain regions were found to be robustly predictive of better cognitive performance in patients and their siblings as well as lower levels of disorganization (6). Hinkley et al. (7) examined how symptoms are related to abnormal connectivity between specific brain regions. In addition to this approach, others have adopted the view that schizophrenia may not be related to abnormalities of specific brain regions but rather be the result of an underlying aberrant organization of the brain network as a whole. Such network studies are motivated by the concept that brain function, and by inference dysfunction of the brain, may not solely be related to the properties of particular brain regions or specific connections but rather emerges from the interactions of the complete network, the so-called brain’s connectome (1). The human connectome is a detailed map of all neural connections of our brain, and the emerging field of connectomics attempts to create and study this comprehensive map of neural circuits on both the microscopic and a whole-brain macroscopic level (1). Landmark studies in this emerging field have shown that the connections of the human brain are not random but rather are organized according to a highly efficient topology (9). The brain’s network combines local information processing with efficient global integration of information between distant parts of the network (9,10), an organization shown to be critical for healthy brain functioning (2). It has been suggested that schizophrenia may be related to an abnormal wiring pattern of the brain, particularly a reduced level of global integration across the network (11). Three studies have revealed evidence for connectome abnormalities in schizophrenia, observing reduced wiring and diminished global efficiency in patients (5,11,12). Consistent with the findings of Hinkley et al. (7), these results suggest an abnormal organization of the brain’s network in patients, with a reduced central hub role of BIOL PSYCHIATRY 2011;70:1107–1108 © 2011 Society of Biological Psychiatry
1108 BIOL PSYCHIATRY 2011;70:1107–1108 frontal regions (5,11). Brain hubs are regions with an above average number of connections that take a central position in the network; they have been suggested to be a focal point for large-scale communication in the human brain (9,10). In this context it has been hypothesized that diminished functioning of key brain hubs in schizophrenia may lead to inefficient information integration between the different regions of the brain (5,11). So far, however, these network studies have not been able to find a clear association between aberrant brain network topology and cognitive symptoms in schizophrenia (5,11,12), as reported in the study by Hinkley et al. (7). Be that as it may, our current knowledge about the brain’s network is just the proverbial tip of the iceberg. Emerging new technology will enable the creation of more detailed connectivity maps and drive discoveries on the fundamental organization of the human connectome and its critical role in the (dys)functioning of the brain. We strongly believe that studying the neural circuits of the brain will ultimately elucidate how the healthy human brain works and consequently help unravel the pathology of many, if not all, psychiatric disorders. A pivotal question remains: where does this abnormal brain connectivity originate? One hypothesis is that abnormal brain wiring may result from aberrant maturation of the connectome during brain development. Currently our knowledge of healthy brain development is limited, certainly regarding the formation of brain connections. Understanding changes in the brain’s connections will be essential in explaining the underlying brain pathology in schizophrenia and possibly that of many other psychiatric disorders. The development of the brain’s network may reflect a shift from a local to a more global organization, in which the level of information integration is optimized between the distant parts of the brain (13). However, many questions about healthy brain development remain, such as the following: what underlying mechanism enforces this shift from a local-to-global orientation, which pathways are involved, what is the role of brain hubs in this process, and in particular how are these processes linked to the maturation of human cognition? Large-scale population imaging, following large number of subjects in a longitudinal setting, provides an opportunity to find answers to these questions. Such studies will provide fundamental knowledge on normal brain maturation, information that will be crucial to generate new ways for early detection of abnormal developmental trajectories leading toward psychiatric illnesses (13).
www.sobp.org/journal
Commentary In summary, the study by Hinkley et al. (7) presents a novel finding on one of the missing links in schizophrenia research, associating as they do abnormal brain connectivity with specific symptoms of the disease. Their study heralds an important new field of study: examining how abnormal brain wiring is related to the development of psychiatric diseases. The authors reported no biomedical financial interests or potential conflicts of interest. 1. Bullmore E, Sporns O (2009): Complex brain networks: graph theoretical analysis of structural and functional systems. Nat Rev 10:186 –198. 2. van den Heuvel MP, Stam CJ, Kahn RS, Hulshoff Pol HE (2009): Efficiency of functional brain networks and intellectual performance. J Neurosci 29:7619 –7624. 3. Stephan KE, Friston KJ, Frith CD (2009): Dysconnection in schizophrenia: from abnormal synaptic plasticity to failures of self-monitoring. Schizophr Bull 35:509 –527. 4. Ellison-Wright I, Bullmore E (2009): Meta-analysis of diffusion tensor imaging studies in schizophrenia. Schizophr Res 108:3–10. 5. Lynall ME, Bassett DS, Kerwin R, McKenna PJ, Kitzbichler M, Muller U, et al. (2010): Functional connectivity and brain networks in schizophrenia. J Neurosci 30:9477–9487. 6. Repovs G, Csernansky JG, Barch DM (2010): Brain network connectivity in individuals with schizophrenia and their siblings. Biol Psychiatry 69: 967–973. 7. Hinkley LBN, Vinogradov S, Guggisberg AG, Fisher M, Findlay AM, Nagarajan SS (2011): Clinical symptoms and alpha band resting-state functional connectivity imaging in patients with schizophrenia: implications for novel approaches to treatment. Biol Psychiatry 70:1134 –1142. 8. Cole MW, Anticevic A, Repovs G, Barch D (2011): Variable global dysconnectivity and individual differences in schizophrenia. Biol Psychiatry 70: 43–50. 9. Hagmann P, Cammoun L, Gigandet X, Meuli R, Honey CJ, Wedeen VJ, et al. (2008): Mapping the structural core of human cerebral cortex. PLoS Biol 6:e159. 10. van den Heuvel MP, Sporns O (2011): Rich-club organization of the human connectome. J Neurosci 31:15775–15786. 11. van den Heuvel MP, Mandl RC, Stam CJ, Kahn RS, Hulshoff Pol HE (2010): Aberrant frontal and temporal complex network structure in schizophrenia: a graph theoretical analysis. J Neurosci 30:15915–15926. 12. Zalesky A, Fornito A, Seal ML, Cocchi L, Westin CF, Bullmore ET, et al. (2011): Disrupted axonal fiber connectivity in schizophrenia. Biol Psychiatry 69:80 – 89. 13. Dosenbach NU, Nardos B, Cohen AL, Fair DA, Power JD, Church JA, et al. (2010): Prediction of individual brain maturity using fMRI. Science 329: 1358 –1361.