1. Joji Nishimura1, Shingo Kakeda1, Osamu Abe2, Reiji Yoshimura3, Junji Moriya1, Naoki Goto3, Hikaru Hori3, Norihiro Ohnari1, Toru Sato1, Shigeki Aoki4, Kuni Ohtomo 2, Jun Nakamura3, Yukunori Korogi1 1) Department of Radiology, University of Occupational and Environmental Health School of Medicine 2) Department of Radiology, Graduate School of Medicine, University of Tokyo 3) Department of Psychiatry, University of Occupational and Environmental Health School of Medicine 4) Department of Radiology, Juntendo University, Tokyo Plasma levels of 3-methoxy-4-hydroxyphenylglycol are associated with microstructural changes within the cerebellum in early stage of first-episode schizophrenia― a longitudinal voxel-based study

2. Introduction The identification of the structural brain abnormalities in patients with schizophrenia, using magnetic resonance (MR) imaging, has become an important area of neuroimaging research in recent years. Several previous studies using a voxel-wise analysis (including voxel- based morphometry; VBM) have reported that the morphological changes were detectable on 3D MR imaging and/or the reduced fractional anisotropy (FA) on diffusion tensor imaging (DTI) in several regions at the first-episode schizophrenia (1). Recently, the many studies have looked at the relationship between structural data (including DTI) and the clinical data (including Positive and Negative Syndrome Scale: PANSS) (2). （ 1 ）. Ananth H.,et al. 2002. Am J Psychiatry. 159: 1497-505. （ 2 ）. Shin, Y.W., et al. 2006. Neuroimage. 30: 1285-91.

3. Introduction For the treatment of schizophrenia, determining whether neural changes continue during the course of the illness is important for understanding its neurobiological features. Plasma homovanillic acid (HVA) and 3-methoxy-4- hydroxyphenylglycol (MHPG) are peripheral catecholaminergic measures, they are good predictors of the response to antipsychotic treatment (3). However, voxel-wise correlation/regression analysis in which correlation between MR data and the peripheral catecholaminergic measures has not been shown. （ 3 ）. Yoshimura R., et al. 2003. Int Clin Psychopharmacol 18:107-11.

4. Purpose This study aimed to determine how the interval changes of the brain structures in early stage of first-episode schizophrenia relate to interval changes of the clinical symptoms and peripheral catecholaminergic measures.

5. Subjects 26 patients Fulfilled DAM-IV-TR criteria (A, B, D, E, and F), but were within 6 months from the onset 6 months follow up 23 of 26 patients Diagnoses of schizophrenia were established. 16 patients Evaluations at the time of baseline and follow-up were available.

6. All 16 patients underwent the following evaluations at the time of baseline and follow-up. MR examination ■ 3D SPGR ■ DTI Peripheral catecholaminergic measures (4)(5) ■ HVA ■ MHPG Clinical symptoms ■ PANSS （ 4 ）. Yeung PKF., et al. 1996. J Pharm Sci. 85: 451-3. （ 5 ）. Minegishi A., et al. 1984. J Chromatgr. 311: 51-7. MRI and Clinical data

7. （ 6 ）. Ashburner J., et al. 2000. Neuroimage 11: 805-21. （ 7 ）. Good C. D., et al. 2001. Neuroimage 14: 21-36. （ 8 ）. Abe O., et al. 2008. Neurobiol Aging 29: 102-16. （ 9 ）. Luders E., et al. 2004. Neuroimage 22: 656-64. MR imaging 3T MR system (Signa EXCITE HD 3T; GE Medical Systems) ■ VBM: 3D SPGR (6-8) TR/TE/NEX=10.1/4.1/1, FOV 24cm, slice thickness 1.2mm, spatial resolution 0.47x0.47x1.2mm. ■ DTI (9) TR/TE/NEX=12000/83.3/1, FOV 26cm, slice thickness 4mm, spatial resolution 1.02x1.02x4mm.

8. (a)(b)(c) (a); Spatial normalization of all images to a standardized anatomical space (b); Extraction of gray and white matter from the normalized images (c); Smoothing SPM5 (Statistical Parametric Mapping 5) Pre-processing: VBM

9. (a)(b)(c) Pre-processing: FA, MD SPM5 (Statistical Parametric Mapping 5) (a); Creation of FA/MD template from the coregisterd FA/MD map applying to the customized T1 templete. (b); All FA/MD maps transformed by registering each of the images to the customized FA/MD templete. (c); Smoothing

10. In order to examine the morphological changes of brain volume, FA and MD, we generated a new set of images (temporal subtracting image: TSI) (10). ■ TSI (baseline image – follow-up image)/0.5(baseline image + follow-up image). baseline (c) follow-up (c) -0.5 baseline (c) follow-up (c) +× (10). Luders E., et al. 2004. Neuroimage. 22: 656-64. Temporal Subtracting Image

11. The threshold was set at uncorrected p <0.001, whereas significance levels were set at corrected p <0.05. TSI Morphological change FA MD Interval changes Laboratory data (HVA and MHPG) Clinical data (PANSS) Correlational analysis (SPM5) Statistical analysis

12. Table: Interval changes of each data base-linefollow-uppaired t-test Mean P age29.0±11.6 Male/Female8/8 Total intracranial volume (ml) 1476.6±123.51484.6±131.00.21 Total GM volume (ml)665.2±61.1665.2±74.40.99 Total WM volume (ml)477.6±57.9482.3±62.20.28 PANSS-P15.5±4.712.8±5.50.07 PANSS-N16.8±5.814.4±4.80.17 BDNF14.1±5.613.5±9.60.83 MHPG4.3±2.05.2±1.40.01 HVA7.2±2.16.3±1.30.001 duration of MR examination (days) 205.6±31.1 Note. —GM=Gray Matter, WM= White Matter, PANSS= Positive and Negative Syndrome Scale Results

13. A positive correlation was observed between the MHPG and the FA in the right cerebellar vermis. No significant correlations between any of the brain volume or MD and any laboratory data, between any MR data (brain volumes, FA, and MD) and PANSS. Results

14. FA values in the patients with first-episode schizophrenia has been lower than those in controls at widespread brain regions (11). A positive correlation between the FA and MHPG was observed in right cerebellar vermis. → Microstructural changes (FA changes) within the cerebellum may relate to the noradrenergic activity during the early stage of first-episode schizophrenia. （ 11 ）. Kanaan RA, et al. 2009. Biol Psychiatry. 66:1067-9. Discussion

15. Many regions of the brain are supplied by the noradrenergic systems. Our positive correlation between FA in the cerebellar vermis and noradrenerin metabolite MHPG may reflect the functional connections in the cerebellum as noradrenergic systems. Noradrenergic systems Discussion Noradrenergic systems

16. Cerebellum shares bidirectional connections with regions of interest to psychiatry through their association with emotional processing (12). Disruption of a cortico-cerebellar-thalamic-cortical circuit (CCTCC) underlies the combination of symptoms observed in schizophrenia (13). （ 12 ）. Middleton FA, et al. 2000. Brain Res Brain Res Rev. 31:236-50. （ 13 ）. Andreasen NC, et al. 1996. Proc Natl Acad Sci U S A. 93: 9985-90. The underlying microstructural changes within the cerebellum in patients with first-episode schizophrenia are present during 6-month follow-up. Discussion Cerebellum in schizophrenia

17. A correlation between the brain volume and any data was not found in any brain region. → Lower sensitivity with brain volume change compared with FA change when assessing the early stage of first-episode schizophrenia. → Short follow-up periods may not allow for brain volume change. A correlation between the longitudinal MR data and PANSS was not found in any brain region. → Antipsychotic medication may have affected the clinical symptom. Discussion Limitations

18. During 6-month follow-up in early stage of first-episode schizophrenia, the MHPG changes were correlated with the microstructural FA changes in the cerebellum, which may reflect the functional connections in the cerebellum as noradrenergic systems. Conclusion