2756

Quantitative Susceptibility Mapping MRI shows changes in dorsal striatum in patients with a first Episode of Psychosis compared to controls.
Marisleydis García1,2,3, Néstor Muñoz1,2,3, Manuel Chappa1,2,3, Carlos Milovic1,2,3, Cristian Montalba2,3,4, Julio Acosta-Carbonero5, Luz María Alliende6, Bárbara Iruretagoyena6, Juan Undurraga7, Alfonzo González7, Carmen Paz Castañeda7, Marcelo Andia2,3,4, Sergio Uribe2,3,4, Nicolas Crossley2,6, and Cristián Tejos1,2,3

1Departament Electrical Engineer, Pontificia Universidad Católica de Chile, Santiago de Chile, Chile, 2Biomedical Imaging Center, Pontificia Universidad Católica de Chile, Santiago de Chile, Chile, 3Millennium Nucleus for Cardiovascular Magnetic Resonance, Santiago de Chile, Chile, 4Radiology Department, School of Medicine, Pontificia Universidad Católica de Chile, Santiago de Chile, Chile, 5Wellcome Centre for Human Neuroimaging, University College London, London, United Kingdom, 6Pontificia Universidad Católica de Chile, Santiago de Chile, Chile, 7Instituto Psiquiátrico Horwitz, Santiago de Chile, Chile

Synopsis

Dopamine is a neurotransmitter that plays an important role in psychosis. Neuromelanin is a by-product of the synthesis of dopamine. In First Episode of Psychosis (FEP) is reported the effect that causes dopamine and its relationship with neuromelanin. However, it has not been reported signal change due to accumulation of heavy metal using magnetic resonance imaging techniques. We found susceptibility changes in two areas of brain using QSM, the left subthalamic nucleus and right caudate. This finding might help to discriminate between FEP patients and healthy subjects.

Introduction

The dopamine hypothesis of psychosis suggests that elevated dopamine synthesis capacity release results in psychotic symptoms1. A recent meta-analysis of PET imaging studies of pre-synaptic dopamine in schizophrenia found signal increases in the striatum, particularly its dorsal part2. Neuromelanin is known to be a by-product of dopamine and noradrenaline metabolism3. It is found predominantly in the dopaminergic neurons of the substantia nigra pars compacta (SNc) and ventral tegmental area (VTA) in the basal ganglia4.

Neuromelamin can interact with many heavy metal ions such as zinc, copper, manganese, chromium, cobalt, mercury, lead, and cadmium and also it binds to iron particularly strongly5. Interestingly, some of them, particularly iron depositions can be assessed by quantitative susceptibility mapping techniques. However, such relationship of neuromelanin and QSM has not been described before in FEP patients.

Here, we examined susceptibility changes in the substantia nigra and basal ganglia of patients with a first episode of psychosis and healthy controls.

Methods

This study included 33 patients (mean age 20 y-o, range 16-24 y-o) who were admitted to hospital with a diagnosis of first episode of psychosis (FEP). All subjects had been exposed less than 3 months to antipsychotic medication, and were considered to be moderately unwell. We also included 22 healthy subjects (mean age 23 y-o, range 15-32 y-o). Subjects were scanned with a 3T Philips Ingenia MR scanner using: 3D Turbo Field Echo (TFE), voxel size: 0.59x0.59x1 mm, TR = 44 ms, TE1 = 7.2 ms, ΔTE = 6.2 ms, bandwidth = 550.5 Hz.

The QSM reconstruction pipeline consisted of:

1. A brain mask extraction from the magnitude image using Brain Extraction Tool of FSL6.

For each echo:

2. Phase unwrapping using a Laplacian operation7.

. Background field removal using Laplacian Boundary Value (LBV)8.

4. Polynomial fit subtraction to remove transmit/receiver offsets.

5. Additional background field removal using Variable Sophisticated Harmonic Artifact Reduction for Phase data (vSHARP) from 1 to 32 voxels9.

QSM maps were reconstructed using an in-house matlab toolbox: FAst Nonlinear Susceptibility Inversion (FANSI)10. We used a weak harmonic function ssTV (Single-Step QSM with a Total Variation)11(figure 1). Lambda parameter was set to 1x10ˆ-4 and harmonic parameter was 0.1 (muh), following an L-curve parameter optimization. Using SPM software12, TFE images were co-registered to the structural T1-w MPRAGE of the subject and normalized with Multi-contrast PD25 atlas13,14,15. A statistical analysis of the regions extracted from the atlas was performed comparing QSM measurements of patients and healthy subjects. The analysis was performed using Mann-Whitney U test, focusing on the basal ganglia and substantia nigra.

Results

We found significant differences between patients and controls in two subcortical regions: left subthalamic nucleus and right caudate. In both regions, the susceptibility values of the patients were lower than that healthy subjects. In left subthalamic nucleus of the patients, this value was -0.009 ± 0.0026 [ppm] and in volunteers was 0.016 ± 0.050 [ppm] (figures 2 and 3). Values for the right caudate were 0.010 ± 0.008 [ppm] and 0.014 ± 0.009 [ppm] (figures 2 and 3) for patients and controls. We found no other significant differences for the remaining evaluated regions (Table 1). However, none of the differences above survived multiple comparisons correction.

Discussion and conclusion

In this study we found significant differences between patients and controls in two regions of brain: right caudate and left subthalamic nucleus. Our finding in the right caudate resonates with the extensive literature in established schizophrenia and prodromal stages of pre-synaptic dopamine synthesis changes16. A previous study also showed a trend of an inverse relationship between pre-synaptic dopamine measured by PET and neuromelanin17. We are currently increasing the sample size to improve the power of our analysis.

Acknowledgements

This publication has received funding from Fondecyt 1161448, Millenium Science Initiative of the Ministry of Economy, Development and Tourism, grant Nucleus for Cardiovascular Magnetic Resonance, Fondecyt 1160736 and Anillo ACT1416.

References

  1. Howes, O. and Kapur, S. (2009). The Dopamine Hypothesis of Schizophrenia: Version III--The Final Common Pathway. Schizophrenia Bulletin, 35(3), pp.549-562.
  2. McCutcheon, R., Beck, K., Jauhar, S. and Howes, O. (2017). Defining the Locus of Dopaminergic Dysfunction in Schizophrenia: A Meta-analysis and Test of the Mesolimbic Hypothesis. Schizophrenia Bulletin, 44(6), pp.1301-1311.
  3. Shibata, E., Sasaki, M., Tohyama, K., Otsuka, K., Endoh, J., Terayama, Y. and Sakai, A. (2008). Use of Neuromelanin-Sensitive MRI to Distinguish Schizophrenic and Depressive Patients and Healthy Individuals Based on Signal Alterations in the Substantia Nigra and Locus Ceruleus. Biological Psychiatry, 64(5), pp.401-406.
  4. Lehéricy, S., Bardinet, E., Poupon, C., Vidailhet, M. and François, C. (2014). 7 tesla magnetic resonance imaging: A closer look at substantia nigra anatomy in Parkinson's disease. Movement Disorders, 29(13), pp.1574-1581.
  5. Perez-Costas, E., Melendez-Ferro, M. and Roberts, R. (2010). Basal ganglia pathology in schizophrenia: dopamine connections and anomalies. Journal of Neurochemistry, 113(2), pp.287-302.
  6. S.M. Smith. Fast robust automated brain extraction. Human Brain Mapping, 17(3):143-155, November 2002.
  7. Schofield, M., & Zhu, Y. (2003). Fast phase unwrapping algorithm for interferometric applications. Optics Letters, 28(14), 1194. doi: 10.1364/ol.28.001194
  8. Zhou D, Liu T, Spincemaille P, Wang Y. Background field removal by solving the Laplacian boundary value problem. NMR in Biomedicine. 2014;27(3):312–319.
  9. Bilgic, B., Fan, A., Polimeni, J., Cauley, S., Bianciardi, M., Adalsteinsson, E., Wald, L. and Setsompop, K. (2013). Fast quantitative susceptibility mapping with L1-regularization and automatic parameter selection. Magnetic Resonance in Medicine, 72(5), pp.1444-1459.
  10. Milovic, C., Bilgic, B., Zhao, B., Acosta-Cabronero, J., & Tejos, C. (2018). Fast nonlinear susceptibility inversion with variational regularization. Magnetic Resonance in Medicine, 80(2), 814-821. doi: 10.1002/mrm.27073.
  11. Carlos Milovic, Berkin Bilgic, Bo Zhao, Christian Langkammer, Cristian Tejos and Julio Acosta-Cabronero. Weak-harmonic regularization for quantitative susceptibility mapping (WH-QSM); Magn Reson Med, 2018;00:1–13. doi: 10.1002/mrm.27483.
  12. Maldjian, J., Laurienti, P., Kraft, R. and Burdette, J. (2003). An automated method for neuroanatomic and cytoarchitectonic atlas-based interrogation of fMRI data sets. NeuroImage, 19(3), pp.1233-1239.
  13. Y. Xiao, V. Fonov, S. Beriault, F.A. Subaie, M.M. Chakravarty, A.F. Sadikot, G. Bruce Pike, and D. Louis Collins, “A dataset of multi-contrast population-averaged brain MRI atlases of a Parkinson’s disease cohort,” accepted in Data in Brief, 2017.
  14. Y. Xiao, V. Fonov, S. Beriault, F.A. Subaie, M.M. Chakravarty, A.F. Sadikot, G. Bruce Pike, and D. Louis Collins, “Multi-contrast unbiased MRI atlas of a Parkinson’s disease population,” International Journal of Computer-Assisted Radiology and Surgery, vol. 10(3), pp. 329-341, 2015.
  15. Y. Xiao, S. Beriault, G. Bruce Pike, and D. Louis Collins, “Multicontrast multiecho FLASH MRI for targeting the subthalamic nucleus,” Magnetic Resonance Imaging, vol. 30, pp. 627-640, 2012.
  16. Jauhar, S., Nour, M., Veronese, M., Rogdaki, M., Bonoldi, I., Azis, M., Turkheimer, F., McGuire, P., Young, A. and Howes, O. (2017). A Test of the Transdiagnostic Dopamine Hypothesis of Psychosis Using Positron Emission Tomographic Imaging in Bipolar Affective Disorder and Schizophrenia. JAMA Psychiatry, 74(12), p.1206.
  17. Ito, H., Kawaguchi, H., Kodaka, F., Takuwa, H., Ikoma, Y., Shimada, H., Kimura, Y., Seki, C., Kubo, H., Ishii, S., Takano, H. and Suhara, T. (2017). Normative data of dopaminergic neurotransmission functions in substantia nigra measured with MRI and PET: Neuromelanin, dopamine synthesis, dopamine transporters, and dopamine D2 receptors. NeuroImage, 158, pp.12-17.

Figures

Table 1. Mean QSM values [ppm] and deviation of patients and healthy subjects. P-value obtained to make the Mann-Whitney U Test.

Fig.1: QSM reconstructions showing significant differences for the right caudate.

Fig 2: Mann-Whitney U test of QSM measurement for patients. 1- Left substantia nigra, 2- Left subthalamic nucleus, 3- Left caudate, 4- Left putamen, 5- Left globus pallidus externa, 6- Left globus pallidus interna, 7- Left thalamus, 8- Right substantia nigra, 9- Right subthalamic nucleus, 10- Right caudate, 11- Right putamen, 12- Right globus pallidus externa, 13- Right globus pallidus interna, 14- Right thalamus.

Fig 3: Mann-Whitney U test of QSM measurement for healthy subjects. 1- Left substantia nigra, 2- Left subthalamic nucleus, 3- Left caudate, 4- Left putamen, 5- Left globus pallidus externa, 6- Left globus pallidus interna, 7- Left thalamus, 8- Right substantia nigra, 9- Right subthalamic nucleus, 10- Right caudate, 11- Right putamen, 12- Right globus pallidus externa, 13- Right globus pallidus interna, 14- Right thalamus.

Proc. Intl. Soc. Mag. Reson. Med. 27 (2019)
2756