REVIEW URRENT C OPINION

Diffusion Tensor Imaging findings and their implications in schizophrenia Marek Kubicki a and Martha E. Shenton a,b

Purpose of review Schizophrenia is a multifocal brain disease that involves abnormal brain connectivity. Diffusion Tensor Imaging is the most advanced imaging technique to investigate white matter connections in vivo. In this review, we focus on studies published in the last year with a high impact on our understanding of how changes in white matter may lead to better treatment. Recent findings Recent studies establish white matter changes at illness onset, and quite possibly before, wherein they constitute a risk factor. Some studies also suggest that white matter changes might not progress over time, even without treatment. Further, while genetic risk may be associated with neurodevelopmental changes related to either white matter geometry, or a different trajectory of aging, clinical risk may also be associated with more acute changes of tissue integrity. These latter changes may be inflammatory in nature at illness onset, and related to the cellular integrity of oligodendrocytes and/or astrocytes at later stages of illness. Summary Recent publications suggest new directions for research and lead to new hypotheses about the pathophysiology of schizophrenia involving white matter. When replicated on larger samples, this knowledge will likely lead to the development of new treatment strategies. Keywords Diffusion Tensor Imaging, inflammation, neurodegeneration, schizophrenia, tract geometry, white matter

INTRODUCTION Although the cause of schizophrenia is still unknown, cumulative evidence suggests that it comprises neurodevelopmental and neurodegenerative components, as well as associated genetic risk (e.g., [1]). Earlier in-vivo imaging studies suggest volumetric deficits in multiple, functionally related brain regions, and one of the leading hypotheses in schizophrenia suggests insufficient, or ineffective communication among brain regions (e.g., [2,3]). Such abnormal communication has been reexamined and confirmed using functional imaging. Additionally, postmortem and genetic studies have demonstrated abnormality that involves both myelin and oligodendrocytes (e.g., [4]), suggesting that abnormal communication and connectivity in schizophrenia might be partially due to anatomical, white matter disconnections among brain regions. This latter theory has led to an increased interest in white matter abnormalities in schizophrenia. However, it has only been since the introduction of Diffusion Tensor Imaging (DTI) that the field has

shown an increase in interest in examining the role of white matter connectivity dysfunctions in schizophrenia. DTI was developed in 1994 [5], and since then it has become the gold standard in clinical investigations of white matter. The method, via the application of specialized gradient pulses, is sensitive to diffusion of water molecules (Brownian diffusion), which, when measured in multiple directions at once, provides an estimation

a Psychiatry Neuroimaging Laboratory, Departments of Psychiatry and Radiology, Brigham and Women’s Hospital, Harvard Medical School, Boston and bVeterans Affairs (VA) Boston Healthcare System, Brockton, Massachusetts, USA

Correspondence to Marek Kubicki, MD, PhD, Psychiatry Neuroimaging Laboratory, Department of Psychiatry, Brigham and Women’s Hospital, Harvard Medical School, 1249 Boylston Street, Boston, MA 02215, USA. Tel: +1 617 525 6234; fax: +1 617 525 6150; e-mail: kubicki @bwh.harvard.edu Curr Opin Psychiatry 2014, 27:179–184 DOI:10.1097/YCO.0000000000000053

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KEY POINTS  White matter abnormality occurs at disease onset, before medication treatment.  White matter changes in chronic schizophrenia are most likely cellular, but might start as a neuroinflammatory process.  Increased risk for developing schizophrenia might be associated with neurodevelopmental changes that involve either microstructure (cells or extracellular space), or macrostructure (brain geometry).  Trajectories of white matter aging might be altered in schizophrenia.

of not only the degree of overall diffusion per measured element (voxel), but also its directionality. Further, depending on the tissue structure, diffusion can be either free (isotropic and unrestricted in all directions, as seen in ventricles, or larger brain lesions filled with fluid), randomly restricted (isotropic and restricted in all directions, as seen in gray matter, or glial scars), or selectively restricted (anisotropic – seen in white matter, wherein higher anisotropy corresponds to more coherent, thicker, or better myelinated axons). This property of DTI, the ability to measure and to compare groups and individuals’ diffusion within white matter structures that are fiber bundles, is the reason for DTI’s popularity in clinical investigations. In fact, since the introduction of DTI, investigators quickly understood that quantitative DTI measures, namely fractional anisotropy and Trace, are very sensitive to even subtle changes in white matter structure (termed integrity). Thus, DTI has been applied to a long list of neuropsychiatric diseases in which white matter involvement has been known, or suspected. These include demyelinating diseases, neurodevelopmental disorders, disorders of communication, disorders involving brain degeneration, metabolic and endocrinology disorders, as well as acute and chronic brain injury, to name just a few. DTI was applied for the first time in schizophrenia in 1998 [6], and since then there have been more than 200 studies published in the field, most of which document white matter abnormality in many different schizophrenia populations. What is not clear, however, is whether these changes occur prior to psychosis onset, suggesting the critical role of neurodevelopment; or at the onset of illness, suggesting that white matter changes are either a trigger or a direct consequence of psychotic onset; or 180

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later on, as a consequence of illness duration, medication treatment or other factors. A very important question that previous publications have not been able to address thus far is, what biological abnormalities underlie the DTI changes observed in schizophrenia? This year’s studies, reviewed below, constitute a more sophisticated understanding of white matter abnormality in schizophrenia, by addressing, at least partially, both the time-course of DTI changes, as well as their possible biological underpinnings. First, we present and discuss DTI findings from large and unique groups of unmedicated first episode patients as well as unmedicated chronic schizophrenia populations. This is followed by a review of DTI changes associated with risk of schizophrenia, along with some quite interesting interpretations. Next, we discuss new approaches to understand better the neurobiology of DTI changes observed in schizophrenia, as well as review studies that suggest some of the possible confounds of DTI research in schizophrenia, including the rarely investigated impact of nicotine, and age and sex on DTI data. Finally, we present our conclusions, and suggest future directions for investigating white matter alterations in schizophrenia.

IS WHITE MATTER ABNORMAL AT THE ONSET OF SCHIZOPHRENIA? Early DTI studies in schizophrenia investigated, almost exclusively, medicated patients. It is clear, however, that antipsychotic medication can alter white matter volume, cell density, and oligodendrocytes, as well as astrocyte count [7,8], and hence alter DTI measurements. Thus, in order to understand white matter changes that are specific to schizophrenia, it is especially important to study patients that are not yet medicated. The most recent DTI studies focus more on ‘first episode’ populations, firmly establishing that white matter abnormality exists in schizophrenia before medication treatment is administered. For example, Henze et al. [9 ] investigated adolescents with a first admission diagnosis of schizophrenia (unmedicated), wherein they showed that even when medication, chronicity, and aging effects are not present, schizophrenia is still associated with white matter abnormalities in the corpus callosum. Another recent study investigating a very unusual population of chronic, unmedicated patients, also suggested that white matter changes in schizophrenia occur before medication treatment. In a study by Liu et al. [10 ], chronically ill (with the duration of illness of 15 years on average), yet still never medicated patients with &

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Diffusion imaging in schizophrenia Kubicki and Shenton

schizophrenia were investigated with DTI using an automated, whole brain analytic method known as Tract Based Spatial Statistics (TBSS). Fractional anisotropy reductions in this population were limited only to the left inferior longitudinal fasciculus (ILF) and the left inferior frontal–occipital fasciculus (IFOF), and no relationships were observed between fractional anisotropy and illness duration or age of onset, suggesting that white matter changes in schizophrenia might not be progressive, when not treated with medication. In another interesting article focusing on first episode, never medicated patients with schizophrenia, Guo et al. [11 ] addressed the relationship between white matter abnormality and clinical profiles. Here, the study included only drug naive patients with paranoid schizophrenia, and demonstrated fractional anisotropy reductions only on the right side (as supposed to the left-sided abnormalities reported by Liu). Such differences clearly emphasize the need for clinically homogenous samples, suggesting that different clinical populations can be characterized by specific, nonspatially overlapping white matter abnormality. &

controls and patients with schizophrenia. These investigators further reported that when studied longitudinally, those who convert to schizophrenia show fractional anisotropy falling to the levels of patients, as opposed to those who did not convert, whose fractional anisotropy stayed the same over time. These findings suggest that some aspects of white matter abnormality might constitute a trait marker for schizophrenia whereas progression of changes might perhaps be used as a predictor of conversion to schizophrenia. Subtle white matter changes in at-risk individuals were also recently reported by Clemm von Hohenburg et al. [15]. In this study, a clinical at-risk population was compared with low-risk control individuals using TBSS. Results revealed white matter changes in several tracts that were previously implicated in schizophrenia, including superior longitudinal fasciculus, cingulum bundle, and corpus callosum. Although the aforementioned studies suggest that clinical risk for schizophrenia is likely associated with fractional anisotropy decrease, genetic, or familial risk studies do not show a similar, straightforward relationship. Here, a study by Boos et al. [16 ] reported that siblings of patients with first episode schizophrenia demonstrated increased, rather than decreased, fractional anisotropy in the arcuate fascicle compared with controls and their sick family members. This same study also demonstrated that when measured longitudinally, the risk population is characterized by steep fractional anisotropy decrease, suggesting accelerated aging trajectories in this population. Whether an increase of fractional anisotropy in genetic-risk populations and a decrease of fractional anisotropy in clinical-risk populations constitute different types of abnormality, or whether they constitute a spectrum of the same abnormality, remains unclear. To this end, in a recently published study from our laboratory [17], and similar to the report by Boos et al. [16 ], we also showed that genetic risk for schizophrenia might be associated with a different age trajectory of white matter changes over time, than is observed in a healthy, low-risk population. This would suggest that whether fractional anisotropy is increased or decreased in an at-risk population depends upon when during brain development the measurements are taken. In fact, there is some evidence to suggest that schizophrenia might be associated with accelerated aging of white matter (i.e., [18]). Further studies are nonetheless needed to understand better the time line and possible neurodevelopmental trajectory of white matter maturation in health, as well as for those at risk for schizophrenia. &&

WHAT HAPPENS BEFORE SCHIZOPHRENIA ONSET? High risk for developing schizophrenia has been associated with gray matter functional and structural abnormalities, similar to those observed in schizophrenia (e.g., [12]). Thus far, a small number of DTI studies have targeted this population in order to determine whether white matter abnormalities exist before schizophrenia onset, constituting a vulnerability factor for developing psychosis. This theory is being tested by evaluating white matter in individuals at either high genetic (familial) or clinical (prodromal) risk for developing schizophrenia. As the rate at which these populations convert to schizophrenia is in both cases relatively low (10–15%), the populations investigated contain both those who will, and those who will never develop schizophrenia, and thus detecting changes that would be directly related to schizophrenia risk is quite challenging (for a review see [13]). Despite these challenges, several important DTI studies investigating individuals at risk for developing schizophrenia were published this last year. Carletti et al. [14 ] studied, for the first time in the same, longitudinal study, individuals at clinical ‘ultra high risk to develop schizophrenia’, and patients with schizophrenia. They demonstrated that at-risk individuals have white matter fractional anisotropy values falling in between healthy &

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NEUROBIOLOGICAL CORRELATES OF DIFFUSION TENSOR IMAGING ABNORMALITY Early DTI reports suggested fractional anisotropy abnormalities in demyelinating diseases, such as multiple sclerosis (e.g., [19]). Accordingly, fractional anisotropy was considered to be a proxy for myelin integrity. Later DTI studies, however, have questioned the specificity of fractional anisotropy to myelin disruptions. More specifically, animal studies have shown that fractional anisotropy decreases only by less than 20% in demyelinated axons [20]. It is now believed that fractional anisotropy, while sensitive to myelin integrity disruptions, may also be modulated by other factors, including tract geometry, axonal coherence, axonal size, and changes in the volume of water spaces surrounding axons. Consequently, several new measures and approaches have been proposed to make in-vivo studies more specific to particular micropathologies. To understand the neurobiology of white matter changes observed in schizophrenia and schizophrenia risk, several recent diffusion studies have applied new methods and measures in order to address the issue of fractional anisotropy nonspecificity. For example, Levitt et al. [21] and Schell et al. [22] investigated the separate contributions of myelin and axonal abnormality to fractional anisotropy abnormalities observed in schizophrenia. Both of these studies used axial (parallel) and radial (perpendicular) diffusivities as proxy measures of axonal and myelin integrity, respectively, and both reported that fractional anisotropy differences can be attributed to changes in perpendicular, but not in parallel diffusivity. These findings suggest that myelin, not axons, constitutes the main source of diffusion abnormality in schizophrenia. Another strategy, however, yielding slightly different conclusions, has been proposed by Mandl et al. [23 ] and Palaniyappan et al. [24], who used a combination of fractional anisotropy, and a nondiffusion measure of magnetization transfer, magnetization transfer ratio (MTR). This latter measure has been shown to be specific to myelin density, and thus the combination of fractional anisotropy and MTR would demonstrate the degree to which myelin abnormality explains fractional anisotropy differences. Although Palaniyappan et al. found fractional anisotropy reduction and concurrent MTR reduction in chronic schizophrenia, Mandl et al. found the opposite relationship in drug naive schizophrenia patients. In this latter study, fractional anisotropy reduction was associated with MTR increase, suggesting axonal or glial, rather than myelin abnormality. &&

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In addition, Du et al. [25 ] used a combination of MTR and another innovative diffusion measure, obtained with proton spectroscopy – N-acetyl aspartate (NAA) diffusivity. The NAA measure was used to quantify diffusivity of the NAA metabolite that can be found in cell bodies (neurons). Results, also indicated both axonal and myelin abnormality in chronic schizophrenia. The sources of this interesting, and at first glance confusing discrepancy in MTR measurement between chronic and first episode populations are perhaps better understood in the context of a recent study by Pasternak et al. [26 ] in our laboratory. Using a new diffusion MRI measure of free-water, we were able to differentiate axonal degeneration (i.e., demyelination) from extracellular white matter abnormalities, the latter likely attributed to neuroinflammation. This study was conducted in a population of first episode schizophrenia patients who demonstrated that while neuroinflammation was distributed across several structures, over the entire brain, neurodegeneration was more restricted, that is confined to the frontal lobes, suggesting that neuroinflammation prevails in the early stages of schizophrenia, and likely precedes demyelination, which is more prevalent later on, during disease progression. &&

IMPORTANT CONSIDERATIONS IN WHITE MATTER SCHIZOPHRENIA RESEARCH Medication and duration of illness, reviewed above, are not the only factors that potentially impact the results of DTI investigations. Several recent publications suggest that changes observed within white matter in schizophrenia might also be confounded by other factors, including age, life style, environmental factors, and so on. This year’s publications have focused on some of these factors. For example, Kochunov et al. [27 ] reported accelerated fractional anisotropy decline with age in schizophrenia, but not in major depression. A similar finding was also reported by Mandl et al. [23 ], suggesting that this effect is better observed in tracts that are maturing later in life, which may be related to oxidative stress-related cytotoxicity. Although both of these studies suggest ‘programmed’ degeneration in schizophrenia, other recent articles focus on neurodevelopment. For example, Giezendanner et al. [28] observed a relationship between season of birth and fractional anisotropy changes in schizophrenia (lower fractional anisotropy in those born in winter). Age of onset in these patients was also associated with fractional anisotropy changes. Additionally, Savadjiev et al. [29 ] focused on neurodevelopmental changes in white matter, and &

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Diffusion imaging in schizophrenia Kubicki and Shenton

their relationship with sex. These investigators suggested sexually dimorphic changes in white matter geometry of the corpus callosum in adolescent patients with schizophrenia, pointing to sex as yet another important, not extensively studied confounder in white matter research. Two additional studies have investigated the relationship between cigarette smoking and white matter abnormality in schizophrenia. Cullen et al. [30], even though not showing direct smoking effects on fractional anisotropy, demonstrated a possible interaction between smoking, intelligence quotient, and schizophrenia. Further, Kochunov et al. [31] showed not only that fractional anisotropy increases shortly after nicotine administration in schizophrenia smokers with low recent smoking exposure, but that it is also associated with sustained attention in patients with schizophrenia. Whether this so-called ‘self-medication’ observed in patients with schizophrenia is a compensatory mechanism in connectivity disruptions caused by white matter abnormality, remains to be seen.

CONCLUSION Although we are still far from a complete understanding of the time-course and biological nature of white matter changes in schizophrenia, enormous progress has been made in this area of scientific inquiry within the last several years. Early DTI studies provided evidence for the existence of white matter abnormalities in schizophrenia. However, it is only in more recent studies that include large and homogenous schizophrenia populations, as well as more precise and more specific measurements, that new light has been shed into the dynamics and possible underlying neurobiology of these white matter abnormalities. For example, this year’s publications that include never medicated first episode as well as chronic patients with schizophrenia, suggest that white matter abnormality occurs at disease onset, but might not be progressive, even if not treated with antipsychotics. Further, while studies suggest that white matter changes in schizophrenia are most likely cellular, it has also been proposed that they might start as a neuroinflammatory process. Another interesting observation is that some changes, but not necessarily of the same biological nature as in fully developed schizophrenia, might appear before schizophrenia onset. Whether they are developmental or degenerative, and whether they involve microstructure (cells or extracellular space), or macrostructure (brain geometry), is an open question. Future longitudinal studies of individuals at risk (both genetic and clinical) for developing

schizophrenia, which include follow-up of those that convert to schizophrenia, would help our understanding of what happens before and around the time of psychotic onset. Although cellular degeneration is suspected, at least in chronic schizophrenia, it is still not clear what population of cells is affected. We also need to understand better the impact of age and sex on white matter architecture and microstructure, both in terms of localization as well as longitudinal changes. Finally, larger and more homogenous groups will allow us to understand the specificity of white matter changes and their association with particular symptoms, or clinical profiles. All this knowledge needs to be translated directly to the development of new treatment strategies. A better understanding of the neurobiology and time-course of schizophreniarelated white matter changes should lead to earlier and more targeted treatment, and a better chance of good recovery. Acknowledgements We gratefully acknowledge the support of the National Institute of Health (R01 AG042512 to M.K., P50MH 080272 to M.E.S.), the Department of Veterans Affairs Merit Award (M.E.S.), the VA Schizophrenia Center Grant (M.E.S.), from the Department of Veterans Affairs. This work is also part of the National Alliance for Medical Image Computing (NAMIC), funded by the National Institutes of Health through the NIH Roadmap for Medical Research, Grant U54 EB005149 (M.K., M.E.S.). Conflicts of interest The authors report no conflicts of interest.

REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Weinberger DR. From neuropathology to neurodevelopment. Lancet 1995; 346:552–557. 2. Wernicke C. Grundrisse der Psychiatrie. Leipzig: Thieme; 1906. 3. Kraepelin E. Dementia Praecox. Barclay SB, editor. New York: Churchill Livingstone Inc.; 1919/1971. 4. Uranova N, Orlovskaya D, Vikhreva O, et al. Electron microscopy of oligodendroglia in severe mental illness. Brain Res Bull 2001; 55:597– 610. 5. Basser PJ, Mattiello J, LeBihan D. MR diffusion tensor spectroscopy and imaging. Biophys J 1994; 66:259–267. 6. Buchsbaum MS, Tang CY, Peled S, et al. MRI white matter diffusion anisotropy and PET metabolic rate in schizophrenia. Neuroreport 1998; 9:425–430. 7. Konopaske GT, Sweet RA, Wu Q, et al. Regional specificity of chandelier neuron axon terminal alterations in schizophrenia. Neuroscience 2006; 138:189–196. 8. Konopaske GT, Dorph-Petersen KA, Sweet RA, et al. Effect of chronic antipsychotic exposure on astrocyte and oligodendrocyte numbers in macaque monkeys. Biol Psychiatry 2008; 63:759–765.

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Schizophrenia and related disorders 9. Henze R, Brunner R, Thiemann U, et al. White matter alterations in the corpus & callosum of adolescents with first-admission schizophrenia. Neurosci Lett 2012; 513:178–182. Findings from this study demonstrate decreased fractional anisotropy in the corpus callosum of unmedicated adolescents with schizophrenia. The study emphasizes the existence of white matter changes independent of medication, chronicity, or age effects. 10. Liu X, Lai Y, Wang X, et al. Reduced white matter integrity and cognitive && deficit in never-medicated chronic schizophrenia: a diffusion tensor study using TBSS. Behav Brain Res 2013; 252:157–163. TBSS study of drug naive schizophrenia patients, ill for 15 years on average. Changes in ILF and IFOF on the left site (reduction of fractional anisotropy only) correlated with speed of processing and learning (visual and verbal). No correlation was reported with illness duration or the age of schizophrenia onset. 11. Guo W, Liu F, Liu Z, et al. Right lateralized white matter abnormalities in & first-episode, drug-naive paranoid schizophrenia. Neurosci Lett 2012; 531:5–9. TBSS study conducted in a population of unmedicated patients diagnosed with paranoid schizophrenia. Fractional anisotropy decrease was reported in several tracts in the right hemisphere. There were no correlations with illness severity. 12. Lencz T, Smith CW, McLaughlin D, et al. Generalized and specific neurocognitive deficits in prodromal schizophrenia. Biol Psychiatry 2006; 59:863–871. 13. Peters BD, Blaas J, de Haan L. Diffusion tensor imaging in the early phase of schizophrenia: what have we learned? J Psychiatr Res [Review] 2010; 44:993–1004. 14. Carletti F, Woolley JB, Bhattacharyya S, et al. Alterations in white matter & evident before the onset of psychosis. Schizophr Bull 2012; 38:1170– 1179. Individuals at ultra high risk of developing schizophrenia (prodromes) had fractional anisotropy values that were intermediate between healthy controls and patients with schizophrenia. Those who converted to schizophrenia (five out of 22) showed diminished fractional anisotropy, compared with those who did not. 15. Clemm von Hohenberg C, Kubicki M, Pasternak O, et al. White matter microstructure in individuals at clinical high risk of psychosis: a whole-brain Diffusion Tensor Imaging Study. Schizophr Bull 2013. 16. Boos HB, Mandl RC, van Haren NE, et al. Tract-based diffusion tensor && imaging in patients with schizophrenia and their nonpsychotic siblings. Eur Neuropsychopharmacol 2013; 23:295–304. Patients with first episode schizophrenia showed no fractional anisotropy changes, whereas their siblings showed higher fractional anisotropy in the arcuate fasciculus. The older the patients, the more fractional anisotropy decreases were found all over the brain. 17. Kubicki M, Shenton ME, Maciejewski PK, et al. Decreased axial diffusivity within language connections: a possible biomarker of schizophrenia risk. Schizophr Res 2013; 148:67–73. 18. Rosenberger G, Kubicki M, Nestor PG, et al. Age-related deficits in frontotemporal connections in schizophrenia: a diffusion tensor imaging study. Schizophr Res 2008; 102:181–188. 19. Filippi M, Cercignani M, Inglese M, et al. Diffusion tensor magnetic resonance imaging in multiple sclerosis. Neurology 2001; 56:304–311. 20. Beaulieu C. The basis of anisotropic water diffusion in the nervous system: a technical review. NMR Biomed 2002; 15:435–455.

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21. Levitt JJ, Alvarado JL, Nestor PG, et al. Fractional anisotropy and radial diffusivity: diffusion measures of white matter abnormalities in the anterior limb of the internal capsule in schizophrenia. Schizophr Res 2012; 136: 55–62. 22. Scheel M, Prokscha T, Bayerl M, et al. Myelination deficits in schizophrenia: evidence from diffusion tensor imaging. Brain Struct Funct 2012; 218:151– 156. 23. Mandl RC, Rais M, van Baal GC, et al. Altered white matter connectivity && in never-medicated patients with schizophrenia. Hum Brain Mapp 2013; 34:2353–2365. Multimodal study shows an increase of MTR and an increase of mean diffusivity in left arcuate fasciculus and right uncinate fasciculus, interpreted as axonal or glial aberrations, not myelin abnormality. This study also observed that tracts that age later in life have different ratios of oligodendrocytes to axons (not myelin to axons), and might be more vulnerable to cytotoxicity (oxidative stress). 24. Palaniyappan L, Al-Radaideh A, Mougin O, et al. Combined white matter imaging suggests myelination defects in visual processing regions in schizophrenia. Neuropsychopharmacology 2013; 38:1808–1815. 25. Du F, Cooper AJ, Thida T, et al. Myelin and axon abnormalities in schizophrenia & measured with magnetic resonance imaging techniques. Biol Psychiatry 2013; 74:451–457. Multimodal study that measured separate pathological processes encompassed by DTI fractional anisotropy changes. Findings showed abnormality in both axons (NAA diffusivity) and myelin (MTR). 26. Pasternak O, Westin CF, Bouix S, et al. Excessive extracellular volume && reveals a neurodegenerative pattern in schizophrenia onset. J Neurosci 2012; 32:17365–17372. Using a new diffusion MRI measure of free-water, these investigators were able to differentiate axonal degeneration (i.e., demyelination) from extracellular white matter abnormalities, the latter likely attributed to neuroinflammation. This study reported neuroinflammation as prominent in first episode schizophrenia, and these investigators suggested that neuroinflammation may be followed by neurodegeneration later on. 27. Kochunov P, Glahn DC, Rowland LM, et al. Testing the hypothesis & of accelerated cerebral white matter aging in schizophrenia and major depression. Biol Psychiatry 2013; 73:482–491. In this study, accelerated fractional anisotropy decline was reported with age in schizophrenia, but not in major depression. Tracts maturing later in life appeared to age faster. 28. Giezendanner S, Walther S, Razavi N, et al. Alterations of white matter integrity related to the season of birth in schizophrenia: a DTI study. PLoS One 2013; 8:e75508. 29. Savadjiev P, Whitford TJ, Hough ME, et al. Sexually dimorphic white matter && geometry abnormalities in adolescent onset schizophrenia. Cereb Cortex 2013; Jan 10. This study used DTI-derived measures of white matter geometry to distinguish between micropathology and macroscopic features of white matter architecture in schizophrenia. Sexually dimorphic changes were observed in the corpus callosum in patients with schizophrenia, which likely reflect neurodevelopmental differences in brain torque and asymmetry. 30. Cullen KR, Wallace S, Magnotta VA, et al. Cigarette smoking and white matter microstructure in schizophrenia. Psychiatry Res 2012; 201:152–158. 31. Kochunov P, Du X, Moran LV, et al. Acute nicotine administration effects on fractional anisotropy of cerebral white matter and associated attention performance. Front Pharmacol 2013; 4:117.

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Diffusion Tensor Imaging findings and their implications in schizophrenia.

Schizophrenia is a multifocal brain disease that involves abnormal brain connectivity. Diffusion Tensor Imaging is the most advanced imaging technique...
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