The largest meta-analysis of white matter brain imaging data related to a psychiatric disorder to date recently identified widespread microstructural differences and systemic disruption of the entire brain’s communication system in schizophrenia patients. This landmark study was conducted by the ENIGMA Schizophrenia DTI Working Group and involved 4,322 individuals (1,963 people with schizophrenia and 2,359 healthy controls) from Australia, Asia, Europe, South Africa, and North America. These findings were first published online, October 17, in the journal Molecular Psychiatry

White matter (WM) consists of myelinated axons that enable different regions of the brain to communicate with one another. A fatty sheath called "myelin" gives white matter its color. Gray matter (GM) represents the neural volume of brain tissue in specific regions.

Historically, GM has been the focus of more scientific research than WM. But this is beginning to change. Increasingly, neuroscientists are more interested in how various brain regions work in concert via the functional connectivity facilitated by white matter and less interested in focusing solely on the gray matter of isolated brain regions. 

The latest ENIGMA white matter study was led by a team of researchers from the University of Southern California (USC) who unearthed that poorly myelinated white matter was present throughout the brains of people with schizophrenia. This discovery of white matter abnormalities throughout the entire brain debunks the long-held hypothesis that schizophrenia is correlated with white matter abnormalities only within the prefrontal cortex and temporal lobes.

Interestingly, the most glaring WM abnormalities were found in the corpus callosum (which facilitates communication between the left and right cerebral hemispheres) and in the frontal portion of the corona radiata, which is central to information processing. 

Courtesy of Paul Thompson, Ph.D., Neda Jahanshad, Ph.D., and Conor Corbin, USC Laboratory of Neuro Imaging, USC Mark and Mary Stevens Neuroimaging and Informatics Institute.
Fiber pathways in the brain are altered in schizophrenia, a mental illness in which patients may experience hallucinations, psychosis and depression.
Source: Courtesy of Paul Thompson, Ph.D., Neda Jahanshad, Ph.D., and Conor Corbin, USC Laboratory of Neuro Imaging, USC Mark and Mary Stevens Neuroimaging and Informatics Institute.

The Enhancing Neuro Imaging Genetics through Meta-Analysis (ENIGMA) Consortium is a network of researchers working together on a range of studies that integrate data from 70 different institutions. The latest ENIGMA paper on white matter abnormalities in schizophrenia was conducted by Sinead Kelly in conjunction with Paul Thompson, Neda Jahanshad, and Conor Corbin from the USC Laboratory of Neuro Imaging (LONI) along with countless collaborators around the globe.

Sinead Kelly is currently a postdoctoral research fellow at Harvard Medical School but served as co-lead author of this study while at the USC Mark and Mary Stevens Neuroimaging and Informatics Institute at the Keck School of Medicine when the study was being conducted. 

In a recent statement about the ENIGMA study, Kelly said: "The issue is that frayed 'ethernet cords' are present everywhere. We can definitively say for the first time that schizophrenia is a disorder where white matter wiring is frayed throughout the brain. These findings could lead to the identification of biomarkers that enable researchers to test patients' response to schizophrenia treatment." Adding, "Our study will help improve the understanding of the mechanisms behind schizophrenia, a mental illness that — left untreated — often leads to unemployment, homelessness, substance abuse and even suicide."

What Is the Link Between Cerebellar White Matter Circuitry and Mental Disorders?  

Life Sciences Database/Wikimedia Commons
Cerebellum (Latin for "little brain") in red. "Cerebellar" is the sister word to "cerebral" and means 'relating to or located in the cerebellum.'
Source: Life Sciences Database/Wikimedia Commons

In recent months, other pioneering research has identified a link between mental illness, atypical white matter circuitry, and functional connectivity of the cerebellum (Latin for “little brain”) with other brain regions. For example, an April 2017 study from the Hariri Lab at Duke University reported that "Structural alterations within cerebellar circuitry are associated with general liability for common mental disorders.” In May 2017, a paper spearheaded by Ole Andreassen and colleagues from the Norwegian Centre for Mental Disorders Research (NORMENT) reported on “Cerebellar volume and cerebellocerebral structural covariance in schizophrenia.” 

Based on both of these studies, which appear to identify a heretofore unrecognized role that the cerebellum might play in neuropsychiatric disorders, I reached out to the USC researchers via email yesterday with the following question: “Did Paul Thompson et al. observe abnormalities of white matter integrity in communication pathways between microzones within either hemisphere of the cerebellum and specific regions of the cerebral cortex in people with schizophrenia?

In an email correspondence, Neda Jahanshad, co-lead author of the latest white matter study and assistant professor of neurology at the USC Mark and Mary Stevens Neuroimaging and Informatics Institute, responded:

“The cerebellum is a very interesting area for many neurological and psychiatric disorders. Unfortunately, with the diffusion imaging quality in many of the clinical or legacy datasets, the cerebellum is very much subject to noise and errors, or even kept out of the field of view of the image entirely. More recent efforts have tried to ensure the cerebellum is included in the diffusion scans as well as the standard MRIs. We expect as imaging technologies improve, we’ll have the ability to do a large-scale study of the cerebellar connections. There are, however, already large-scale efforts in place at ENIGMA to look at the structure of the cerebellum in greater detail and to compare differences that may be seen in patients on average more than controls. The connections are a future goal.”

I also asked Neda Jahanshad, “Can the USC researchers explain the significance of identifying a correlation between schizophrenia and “frayed wiring” of the white matter communication networks of the entire brain?” Jahanshad responded via email:

“For brain-related disorders, it is important to know what brain regions are affected, as this knowledge may give us insight into the more functional aspects, such as cognitive and behavior conditions or other symptoms. Knowing what brain regions are involved can also help us focus treatment efforts on those regions of the brain or the pathways of the brain that are involved. These treatments can vary, of course, to include non-pharmaceutical interventions, but knowing the brain region that is affected allows us to look into the cell types of that region — or the genes related to it — and these factors can help in the development of medications specifically for those brain regions.

What we are showing now has been hypothesized for some time: Schizophrenia is a disorder related to brain dysconnectivity. We are seeing that it is not one or two connections that are affected, but the entire communication network of the brain — from large regions to small regions. These affects are not noticeable when we try to compare a few patients to a few controls. However, they are seen when we can combine efforts across countries and continents. We now know this effect in the entire brain is seen around the world, and this is extremely important if we want to develop ways of helping patients everywhere.

There are genes, for example, that may help determine a more global brain-wide connectivity pattern. ENIGMA is actively working on identifying the genes that help determine brain structure and connectivity. Now that we know that the full brain connectivity is disrupted, we may want to look for more effective treatment options through genes relating to the full white matter connection profile, as opposed to genes expressed only in specific regions.”

In a statement, Jahanshad noted: "Previous studies did not always point to the same brain regions. Scientists need to come to a consensus before they can begin looking for answers. To do that, they need to aggregate and analyze global brain scan data. Without this study, future research could have been misdirected."

Neda Jahanshad concludes, "Rather than looking for genes that affect a certain 'stretch of wiring,' scientists will now look for genes that affect the brain's entire communication infrastructure. We're showing that just studying a single brain region to try to find out what causes schizophrenia is not a good approach. The effect is global. Focusing on a certain part of the brain where you think that effect will be is not going to give you the whole story."

References

"Widespread white matter microstructural differences in schizophrenia across 4322 individuals: results from the ENIGMA Schizophrenia DTI Working Group." Molecular Psychiatry (Advance online publication: October 17, 2017) DOI: 10.1038/mp.2017.170

Contributing ENIGMA authors: S. Kelly, N. Jahanshad, A. Zalesky, P. Kochunov, I. Agartz, C. Alloza, O.A. Andreassen, C. Arango, N. Banaj, S. Bouix, C.A. Bousman, R.M. Brouwer, J. Bruggemann, J. Bustillo, W. Cahn, V. Calhoun, D. Cannon, V. Carr, S. Catts, J. Chen, J-x Chen, X. Chen, C. Chiapponi, Kl K. Cho, V. Ciullo, A.S. Corvin, B. Crespo-Facorro, V. Cropley, P. De Rossi, C.M. Diaz-Caneja, E.W. Dickie, S. Ehrlich, F-m Fan, J. Faskowitz, H. Fatouros-Bergman, L. Flyckt, J.M. Ford, J-P Fouche, M. Fukunaga, M .Gill, D.C. Glahn, R. Gollub, E.D. Goudzwaard, H. Guo, R.E. Gur, R.C. Gur, T.P. Gurholt, R. Hashimoto, S.N. Hatton, F.A. Henskens, D.P. Hibar, I.B. Hickie, L.E. Hong, J. Horacek, F.M. Howells, H.E. Hulshoff Pol, C.L. Hyde, D. Isaev, A. Jablensky, P.R. Jansen, J. Janssen, E.G. Jönsson, L.A. Jung, R.S. Kahn, Z. Kikinis, K. Liu, P. Klauser, C. Knöchel, M. Kubicki, J. Lagopoulos, C. Langen, S. Lawrie, R.K. Lenroot, K.O. Lim, C. Lopez-Jaramillo, A. Lyall, V. Magnotta, R.C.W. Mandl, D.H. Mathalon, R.W. McCarley, S. McCarthy-Jones, C. McDonald, S. McEwen, A. McIntosh, T. Melicher, R.I. Mesholam-Gately, P.T. Michie, B. Mowry, B.A. Mueller, D.T. Newell, P. O’Donnell, V. Oertel-Knöchel, L. Oestreich, S.A. Paciga, C Pantelis, O. Pasternak, G. Pearlson, G.R. Pellicano, A. Pereira, J. Pineda Zapata, F. Piras, S.G. Potkin, A. Preda, P.E. Rasser, D.R. Roalf, R. Roiz, A. Roos, D. Rotenberg, T.D.Satterthwaite, P. Savadjiev, U. Schall, R.J. Scott, M.L. Seal, L.J. Seidman, C. Shannon Weickert, C.D. Whelan, M.E. Shenton, J.S. Kwon, G. Spalletta, F. Spaniel, E. Sprooten, M. Stäblein, D.J. Stein, S. Sundram, Y. Tan, S. Tan, S. Tang, H.S. Temmingh, L.T. Westlye, S. Tønnesen, D. Tordesillas-Gutierrez, N.T. Doan, J. Vaidya, N.E.M. van Haren, C.D. Vargas, D. Vecchio, D. Velakoulis, A. Voineskos, J.Q. Voyvodic, Z. Wang, P. Wan, D. Wei, T.W. Weickert, H. Whalley, T. White, T.J. Whitford, J.D. Wojcik, H. Xiang, Z. Xie, H. Yamamori, F. Yang, N. Yao, G. Zhang, J. Zhao, T.G.M. van Erp, J. Turner, P.M. Thompson and G. Donohoe.

"Cerebellar volume and cerebellocerebral structural covariance in schizophrenia: a multisite mega-analysis of 983 patients and 1349 healthy controls." T. Moberget, N. T. Doan, D. Alnæs, T. Kaufmann, A. Córdova-Palomera, T. V. Lagerberg, J. Diedrichsen, E. Schwarz, M. Zink, S. Eisenacher, P. Kirsch, E. G. Jönsson, H. Fatouros-Bergman, L. Flyckt, KaSP, G. Pergola, T. Quarto, A. Bertolino, D. Barch, A. Meyer-Lindenberg, I. Agartz, O. A. Andreassen and L. T. Westlye. Molecular Psychiatry (Advance online publication: May 16, 2017) DOI: 10.1038/mp.2017.106

"Structural Alterations within Cerebellar Circuitry are Associated with General Liability for Common Mental Disorders." Adrienne L. Romer, Annchen R. Knodt, Renate Houts, Bartholomew D. Brigidi, Terrie E. Moffitt, Avshalom Caspi and Ahmad R. Hariri. Molecular Psychiatry (Advance online publication: April 11, 2017) DOI: 10.1038/MP.2017.5

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