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Linear and non-linear brain changes over the transition to psychosis: the BrIT study.

Background In the past decade there has been great interest in studying young people at ultra-high risk for psychotic illnesses such as schizophrenia. These people are at hugely increased risk because of a combination of symptoms and personal or family history. An approach that is now used around the world is to recruit young people who are help-seeking and presenting with clinical symptoms that are similar to those seen in psychotic disorders but attenuated in intensity or frequency1. Such people are said to exhibit an at-risk mental state (ARMS). Around 20% develop psychosis within 12 months of being identified. There are differences in the brains of at-risk cases when compared to similar participants not at risk. These brain differences get greater with the onset of psychotic illness. It is uncertain when in the progression these changes occur. The changes may come before (and somehow cause) the increase in symptoms, implying that trying to prevent those brain changes could prevent the illness. Researchers have found it problematic to predict who eventually develops psychosis. There are currently a high number of false positives who are potentially exposed to unnecessary treatment and stigma. A recent approach adopted from dementia research has used brain scans in complex statistical analyses to improve prediction of psychosis from around 20% to 80%. However, this has only used a single time point. By comparing the trajectory of brain changes between those who do and those who do not develop psychosis, we hope to determine the relationship between progression of symptoms and alterations in brain structure. Ultra-high risk research The identification of people at increased risk of developing psychotic disorders such as schizophrenia, has served a combined purpose of preventing (or at least delaying) the onset of illness, but also determining biological and psychosocial predictors of transition. Initially this work focused on people at elevated risk due to a family history of psychotic disorder, but because the transition rate is still low this work requires large samples and long follow-up times. The rate at which such individuals develop first episode psychosis varies, but a recent meta-analysis of over 2500 individuals places it at 22% over a twelve month period2. This is much higher than the rate in the general population and allows a range of longitudinal studies which were previously unfeasible. Structural changes across the psychotic transition Relatively little is known about the pathological processes that take place during the transition from ARMS to first episode psychosis. To date, the only longitudinal imaging data across this transition are volumetric, and all suggest progressive brain changes with the development of frank illness. The earliest report was a small voxel-based morphometry (VBM) study3, which showed significant reductions in grey matter within temporal and frontal regions. These changes were not seen in patients who did not transition. These findings were subsequently replicated by another group4. However, while being landmark studies, these reports have significant limitations, the primary one being that the changes seen in those who transitioned were not significantly different from changes in those who did not. Other problems included relatively thick image slices, small sample size, and concerns about registration and the VBM approach per se5. To address some of these issues, two approaches
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were combined cortical pattern matching6 and a longitudinal cortical surface motion technique7,8 that allowed examination of changes over time at the submillimetre level with improved image registration. In this analysis9, significant reductions were again demonstrated in patients who developed psychosis. Importantly, the region of significant change (the right prefrontal cortex) matched the findings in first episode psychosis10 and other studies in ARMS11. Predictive utility of structural brain changes Overall there is good evidence for the presence and progression of volumetric brain abnormalities in ARMS. Such abnormalities (both cross-sectional and longitudinal) also seem to have good prognostic utility when incorporated into multivariate predictors of disease transition. In particular, support-vector machines (SVMs) have been successfully employed to predict a subsequent onset of frank psychosis in two independent cohorts of at-risk individuals12,13. Their theoretically and empirically founded ability to learn generalizable discriminative rules in high dimensional data spaces have led to an increasing number of seminal applications (1) in the MRI-based prediction and differential diagnosis of neurodegenerative diseases, such as Alzheimers Disease14,15, Huntingtons Disease16 and Parkinsons disease17, as well as in the imaging-based diagnosis of established schizophrenia18,19. Furthermore, recent analyses suggest that machine learning methods including SVMs and their Bayesian counterparts, the Relevance-Vector Machines are able to learn discriminative/predictive rules across different centres and scanners. These observations are of crucial importance for a real-world clinical application of these methods within the framework of services specializing in early detection and intervention. In the context of this accumulating empirical evidence, SVM-based machine learning applications are very likely to provide the optimal statistical machinery in order to detect those subtle morphological signatures that separate the true prodromal from the broader vulnerability stage of psychosis at the single subject level. Beside their clinical utility, the application of SVMs in the context of the proposed research may significantly further our understanding of the complex intermediate phenotypes that form the neurobiological underpinnings of emerging psychosis. Due to their intrinsic ability to model the brain as a network of interconnected neural elements they typically outperform conventional univariate statistical methods in detecting abnormality patterns associated with certain disease phenotypes both at the cross-sectional as well as at the longitudinal perspective. A complementary approach network connectivity The human brain is a complex patchwork of interconnected regions and it has been shown that deficits in access, engagement and disengagement of large-scale neurocognitive networks play a critical role in disorders such as schizophrenia, depression, and anxiety20. Evidence for dysconnectivity across all stages of the Schizophrenia has been published21, suggesting that this approach may represent an important complementary analysis to more traditional structural comparisons. Functional connectivity is defined as the correlation in activity between spatially distant brain regions. It can be assessed in a number of ways, but one particularly fruitful approach is to
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adopt a graph-theoretical analysis to characterise the topology, modularity and hierarchy of the entire brain as a single network22. Graph-theoretical analyses have shown that individuals with schizophrenia have disrupted small world network organization, which means the balance between local and global connectivity is abnormal. This results in a less integrated and more diverse functional connectivity23, and has been described as a subtle randomization of global network topology24. Only one study has investigated graph theoretical measures in ARMS patients25. While there were no global network differences, there was significantly less involvement of the anterior cingulate in task-relevant network organization26. While this is an important study given it is the first to use a graph theoretical approach in ARMS individuals, it was unusual in that the analysis grouped the ARMS patients into high and low symptoms cohorts on the basis of a median split. No study has yet compared people at risk on the basis of their later psychotic outcome, or been able to assess longitudinal change over the transition to illness. Given the existing data we would predict that global network measures would be the most likely to show progression with the onset of psychosis. Effects of medication It is possible that findings of grey matter loss over the transition to psychosis are due to medication effects (i.e., the possible toxic effect of early introduction of neuroleptic medication) and not (or not solely) neurobiological processes associated with progression of the illness itself. It is certainly the case that long-term neuroleptic treatment of primates has a widespread effect on brain volume27,28. However, whether the same effects are found in humans is unclear. It is now widely accepted that treatment with so-called typical medications produces hypertrophy of the basal ganglia in people with schizophrenia29, which is reversible when patients are switched to an atypical neuroleptic37. Indeed, there is also evidence that such medications can affect brain regions, such as the frontal cortex, that are frequently reported to be abnormal in people with the illness38. However, significant volumetric reductions have also been found across the brain in patients who are neuroleptic-nave30, and furthermore, progressive brain changes can occur in the absence of medication31. The only study to specifically examine whether changes across the transition to psychosis are the same in medicated and un-medicated patients found no significant differences, although it was probably underpowered for this analysis4. In this study we will have the ability to map the trajectory of brain changes directly onto the medication history of each participant, and will therefore be able to demonstrate the extent to which they are related. Summary This study will be the first to acquire brain images at multiple time points over the transition to psychosis in a group of people at ultra-high risk for the disorder. As a result we will be able to demonstrate the precise trajectory of brain changes as the illness develops, including the extent to which the changes precede worsening symptoms and how much they are due to the provision of neuroleptic treatment. Furthermore, we will acquire the first longitudinal data on functional connectivity during this stage of illness, significantly extending our understanding of the neurobiology of psychotic disorders.
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Aims and objectives The main aim of the study is to better understand the brain changes that occur during the transition from the at-risk mental state to frank psychotic illness, and to establish to what extent these changes can be used to improve early detection of individuals at greatest risk. Thus, the study could lead to better targeting of therapeutic interventions aimed at preventing or at least ameliorating the onset of psychotic disorders such as schizophrenia. Specifically, this project will: 1) Determine the trajectory of brain changes across the transition from the at-risk mental state to frank psychotic disorder, both in terms of brain structure and brain connectivity. In particular, we wish to discover whether the changes are nonlinear, with a more rapid rate of change around the time of transition. 2) Establish the power of brain change over time to improve the prediction of transition using support vector machine learning. Study Design We propose to recruit young people at ultra-high risk for psychosis and matched healthy volunteers. Those at risk will be recruited from the Early Detection and Intervention Team (ED:IT) clinics at the Birmingham and Solihull Foundation Mental Health Trust. ED:IT provides clinical service for help-seeking young people aged 16-35 years presenting with attenuated psychotic symptoms and/or a family history of schizophrenia or personal history of schizotypal personality disorder. The recruitment procedure will take place as follows: we will liaise with the clinical team at ED:IT to recruit individuals who are at risk of psychosis. Once potential participants have been highlighted identified we will contact them either by letter or telephone to provide information regarding the study's objectives and methods and obtain consent. If they need more time to consider their participation, the researcher will re-approach them at a later date, with no time restrictions given. We will write to the clinical team and the participant's GP to inform them of the participant taking part in the study. We will meet regularly with the clinical team to discuss study progression and recruitment. Healthy control participants will be recruited through advertisements and through the service-users themselves (i.e. friends). Service-users and their matched healthy peers will be asked to consent to participation in a longitudinal imaging study to determine the neurobiological course of transition to psychotic illness. All participants will be clinically assessed and scanned at baseline and followed up after 12 months, irrespective of whether they remain with the clinical service. Furthermore, the healthy volunteers and a subset of the ARMS group will be assessed consecutively for 6 months (once every month) and then at 9 and 12 months (see ARMS Enrichment Strategy). Participants Participants will be young people aged between 16 and 35. The ED:IT team sees an average of 70 ARMS patients per year. Given the likely number ineligible for the study and the predicted refusal rate, we expect to recruit a total of 120 patients over a period of 30 months. Healthy volunteers will be recruited from similar socio-demographic areas as the ARMS patients, and will be matched as far as possible for age and sex. Individuals who are unable to
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provide informed consent or lack English capacity to complete the assessment will be excluded from the study. Due to limited funding, translators will not be used. Further exclusion criteria will include the presence of a neurological disorder such as epilepsy; history of head injury involving loss of consciousness over 5 minutes or overnight hospital stay, claustrophobia and contraindications for MRI such as a pacemaker. Additional exclusion criteria for the healthy participants will be a personal history of mental illness and a family history of a psychotic illness in a first degree relative. Methods & procedure Baseline assessment All participants will be clinically assessed using the Comprehensive Assessment of the AtRisk Mental State (CAARMS1) by a skilled interviewer, to determine that they meet criteria for ARMS. The presence of other mental illness will be determined using the Structured Clinical Interview for DSM-IV36 (SCID-1). Current non-psychotic symptoms will be measured with the Scale for the Assessment of Negative Symptoms38 and the Brief Psychiatric Rating Scale39. The participants current or absent use of substances will be assessed using the Substance Use Questionnaire. Functioning will be assessed using the Scale of Occupational and Functional Assessment40 (SOFAS), the Global Functioning Role Scale41, the Global Functioning Social Scale42, and the Global Assessment of Functioning Scale43. A series of self-report measures will also be administered to gather demographic information and examine the participants mental state. These include measures of depression such as the Depression Anxiety Stress Scale44 (DASS) and the Centre for Epidemiologic Scale for Depression, Revised45 (CES-D-R). The Dissociative Experience Scale, version 246 (DES-II) will be used to examine dissociative symptoms. Finally, schizotypal traits will be investigated using the SPQ-B47. Additionally at baseline the Childhood Trauma Questionnaire48 (CTQ) will be used to index childhood trauma and neglect. We are interested in looking at the effect of early trauma on the transition to psychosis. Neuroimaging will be conducted using the 3T Phillips Achieva scanner at the Birmingham University Imaging Centre. T1 volumetric data will be collected using a standard anatomical SPGR sequence giving isometric 1mm voxels. Resting state fMRI data will be collected with an echo planar image gradient-echo pulse sequence covering the entire brain. Whilst in the scanner the participant will also complete a working memory (n-back) task. They will be presented with a sequence of letters, and the task consists of indicating when the current letter matches the one presented earlier in the sequence. While the anatomical scan and resting state fMRI are acquired during each visit, the working memory task will only be administered at baseline, 6 months and 12 months follow up. The initial and 12 month procedures will take around two-four hours to complete. The additional six monthly consecutive assessments and the nine month assessment will take around two-three hours to complete. Participants will receive 20 in recognition of their time and effort each time they take part. ARMS Enriching Strategy The driving research question for this study requires scans at multiple time points from those individuals who develop psychosis. While this could be accomplished by rescanning all
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recruited participants, this would not be a particularly feasible strategy. In order to be sure of recruiting a sufficiently large transition group, many individuals would need to be enrolled, and since the majority of ARMS patients do not later develop psychosis, many participants would experience an unnecessary research burden. It is therefore necessary to adopt a strategy that will maximize the proportion of ARMS in our repeat-scan group who transition to psychosis. We propose to utilize two complementary approaches. The first makes use of the clinical features that best predict transition. In the NAPLS (US) study of 291 ARMS49, five baseline variables were significant and unique predictors of psychosis onset within a 2.5-year follow-up period (genetic risk with functional decline, unusual thought content, suspicion/paranoia, low social functioning, and substance abuse). Thompson and colleagues recently applied these factors to an independent sample of 104 ARMS (41 ARMS-P)50. Having any two of unusual thought content, low functioning and genetic risk, increased the positive predictive value to 65.2% with reasonable sensitivity. Individuals from the ARMS group will therefore be selected for more intensive assessment when they present with at least two of the following clinical features 1) genetic risk for schizophrenia with recent functional decline or persistent low social functioning, 2) unusual thought content, and 3) suspicion/paranoia. The second enrichment strategy makes use of recent advances in machine learning algorithms to improve predictive accuracy for psychotic transition. The utility of neuroimaging based multivariate pattern recognition algorithms (such as the support vector machine, or SVM) for this purpose has been recently demonstrated by one of the investigators1,11,13. In this approach, neuroanatomical features derived from structural brain images are used by the SVM to determine the best nonlinear classification model that reliably predicts outcome group membership. Importantly, there is now evidence that a model developed on one set of subjects can be applied to a different set (acquired in another clinic and with a different scanner) and have sensitivity and specificity of over 80%. We will therefore use an SVM model recently produced from data collected in Melbourne and Munich to predict which members of the prospectively collected ARMS group in this study will be most likely to develop psychosis, and select them for more intensive assessment. Because there is as yet no agreement on whether clinical or neuroanatomical features will be most useful in the long run for improving prediction of transition, we will be using both approaches independently. In regards to inclusion in the ARMS group, meeting either or both of the clinical or imaging enrichment criteria is sufficient. Given the current transition rate at ED:IT (20% in 12 months), and the positive predictive value of the enrichment strategies (around 80%), we expect 48 ARMS patients to be selected for multiple assessments, of whom 24 will transition to psychosis. A similar number of matched controls will also be assessed at the same frequency. Longitudinal assessment All participants will be scanned and clinically assessed at 12 months following baseline assessment. A subset of service users and control participants will be selected for intensive assessment, whereby they will be assessed more frequently. Assessments will commence consecutively for six months, then at 9 and 12 months following baseline. At each time point baseline assessments will be repeated. The SCID-136 will only be repeated if the research team has received information from the service users clinician that they suspect that the
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individual has developed further mental health difficulties compared to baseline. As a result the duration of the clinical interview will be approximately an hour shorter at follow up. The neuroimaging assessment will take approximately 35 minutes. However, the duration of the initial, six and 12 month imaging assessments will take approximately 45 minutes because they also contain the n-back task. Where a participant develops a frank psychotic illness, the next assessment will be brought forward to occur as soon as possible after transition. Medication will be recorded based on the prescribed doses noted by clinicians, on a day-byday basis, to allow investigation of the impact of neuroleptics on brain change. Analysis Structural imaging analysis To capture the dynamics of the pathological processes before and just after transition to psychosis, the linear mixed-model regression approach as used by Shaw et al.51 will be employed. This method allows inclusion of multiple scans per individual, and is robust for missing data and irregular intervals between scans. Subjects will be divided into three groups: ARMS who transition, ARMS who do not transition, and healthy controls. Polynomial models for changes in cortical thickness and subcortical volume over time will be tested and compared between the groups. Statistical maps will be threshold for multiple comparisons using the false discovery rate (FDR) procedure and t-statistics will be visualised by projection onto a standard brain template to show clusters of cortical points that significantly differ between the groups over time. The statistical package R (http://www.r-project.org/) and SPSS for Windows (SPSS Inc., Chicago, Ill) will be used to perform the statistical analyses. Furthermore, longitudinal structural brain changes associated with different clinical courses will be analysed by means of a hybrid SVM-Hidden Markov Model (SVM-HMM) that describes brain trajectories as Markov chains, where each node of the chain is defined by a staging SVM model. These node SVMs learn those structural brain patterns that allow differentiating between different clinical phenotypes (e.g. conversion or non-conversion phenotypes) at a given time point in the development of psychosis. The node SVMs decision outputs are translated into emission probabilities which are used by the HMM in order to model transition probabilities within the Markov chain. A new subjects probability of transition to psychosis can thus be effectively determined depending on its position on the structural brain trajectory that is modelled by the SVM-HMM. Connectivity We will use a graph analytic approach24 to measure the topological properties of each individuals functional brain network. In this framework, the brain is modelled as a graph comprising nodes, one per anatomical region, connected by edges, determined by interregional correlations. The nodes can be defined at the voxel level52, region level53, or intermediate scales54. For the current analysis, we will parcellate each participants cortex into 1041 discrete regions using an approach similar to that used by previous authors55. We have previously found that this approximate resolution of analysis provides a good trade-off between computational speed, spatial resolution, and signal-to-noise ratio. There are number of network measures that may be sensitive to changes in the network structure of ARMS patients. We will focus on the three that have been found to be altered in patients with schizophrenia: power-law coefficient (hierarchy), degree correlation
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(assortativity), and mean (Euclidean) connection distance56. Each measure is based on a binarised correlation matrix, and a summary value is created by averaging over a range of 'wiring costs' (binarisation thresholds). For each measure, this provides a single value per subject per visit, and which can be treated like any of the clinical measures, subject to longitudinal analysis as described above. References 1. 2. 3. 4. 5. 6. Yung et al. Australian and New Zealand Journal of Psychiatry. 2005;39:964-971. Fusar-Poli et al. Archives of General Psychiatry. 2012;69:220-229. Koutsouleris et al. Schizophrenia Research. 2010;123:175-187. Wood et al. Schizophrenia Bulletin. 2008;34(2):322-329. Pantelis et al. The Lancet. 2003;361:281-288. Thompson et al. Proceedings of the National Academy of Science. 2001;98(20):11650-11655. 7. Smith et al. Journal of Computer Assisted Tomography. 2001;25(3):466-475. 8. Smith et al. NeuroImage. 2002;17:479-489. 9. Sun et al. Schizophrenia Research. 2009;108:85-92. 10. Sun et al. Molecular Psychiatry. 2009;14:976-986. 11. Koutsouleris et al. British Journal of Psychiatry. 2009;195:218-226. 12. Koutsouleris et al. Schizophrenia Bulletin. 2011; doi:10.1093/schbul/sbr145. 13. Koutsouleris et al. Archives of General Psychiatry. 2009;66:700-712. 14. Klppel et al. Brain. 2008;131:681-689. 15. Davatzikos et al. Neurobiology of Aging. 2008;29:514-523. 16. Klppel et al. Neurology. 2009;72:426-431. 17. Duchesne et al. Academic Radiology. 2009;16:61-70. 18. Davatzikos et al. Archives of General Psychiatry. 2005;62:1218-1227. 19. Ardekani et al. Human Brain Mapping. 2011;32:1-9. 20. Mwangi et al. Brain. 2012;135:1508-1521. 21. Broyd et al. Neuroscience and Biobehavioural Reviews. 2009;33:279-296. 22. Friston.. Schizophrenia Research. 1998 1998;30:115-125. 23. Pettersson-Yeo et al. Neuroscience and Biobehavioural Reviews. 2011;35:1110-1124. 24. Bullmore & Sporns. Nature Reviews Neuroscience. 2009;10:186-198. 25. Lynall et al. Journal of Neuroscience. 2010;30:9477-9487. 26. Rubinov et al. Human Brain Mapping. 2009;30:403-416. 27. Alexander-Bloch et al. Cerebral Cortex. 2012;in press. 28. Lord L-D et al. NeuroImage. 2011;56:1531-1539. 29. Dorph-Petersen et al. Neuropsychopharmacology. 2005;30:1649-1661. 30. Konopaske et al. Neuropsychopharmacology. 2007;32:1216-1223. 31. Navari & Dazzan. Psychological Medicine. 2009;39:1763-1777. 32. Smieskova et al. Current Pharmaceutical Design. 2009;15:2535-2549. 33. Dazzan et al. Neuropsychopharmacology. 2005;30:765-774. 34. Leung et al. Schizophrenia Bulletin. 2011;37:199-211. 35. Job et al. NeuroImage. 2005;25:1023-1030. 36. First et al. Structured Clinical Interview for DSM-IV Axis I Disorders. Washington DC:American Psychiatric Press; 1997. 37. Maxwell. Unpublished manual for the FIGS. Clinical Neurogenetics Branch, Intramural Research Program, National Institute of Mental Health.1992. 38. Andreasen. The scale for the assessment of negative symptoms (SANS). Iowa City: The University of Iowa; 1983.
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39. Overall & Gorham. Psychological Reports. 1962 1962;10:799-812. 40. Goldman et al. The American Journal of Psychiatry. 1992;149:1148-56. 41. Nienda et al. Global Functioning: Role Scale. Los Angeles, CA: University of California, (2006). 42. Auther et al. Global Functioning: Social Scale. Glen Oaks, NY: Zucker-Hillside Hospital (2006). 43. Hall. Psychometrics. 2006;36, 3, 267-75. 44. Lovibond &Lovibond. Behaviour Research and Therapy, 1995: 33, 3, 335-343. 45. Radloff. Applied Psychological Measurement. 1977: 1, 3, 385-404. 46. Bernstein et al. Journal of Nerv. Ment. Dis. 1986:174, 12, 727-35. 47. Raine & Benishay. Journal of personality disorders. 1995:9(4):346-55. 48. Bernstein et al. Child Abuse and Neglect. 2003: 27(2):169-90. 49. Cannon et al. Archives of General Psychiatry. 2008;65(1):28-37. 50. Thompson et al. Schizophrenia Research. 2011;126:51-57. 51. Shaw et al. Nature. 2006;440:676-679. 52. van den Heuvel et al. NeuroImage. 2008;43:528-539. 53. Achard et al. Journal of Neuroscience. 2006;26(1):63-72. 54. Fornito et al. Journal of Neuroscience. 2011;31:3261-3270. 55. Honey et al. Proceedings of the National Academy of Science. 2009;106:2035-2040. 56. Bassett et al. Journal of Neuroscience. 2008;28:9239-9248.

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