Hostname: page-component-78c5997874-m6dg7 Total loading time: 0 Render date: 2024-11-15T01:26:17.524Z Has data issue: false hasContentIssue false

Frontostriatal functional connectivity and striatal dopamine synthesis capacity in schizophrenia in terms of antipsychotic responsiveness: an [18F]DOPA PET and fMRI study

Published online by Cambridge University Press:  21 November 2018

Seoyoung Kim
Affiliation:
Department of Neuropsychiatry, Seoul National University Bundang Hospital, Gyeonggi-do, Republic of Korea
Wi Hoon Jung
Affiliation:
Department of Psychology, College of Liberal Arts, Korea University, Seoul, Republic of Korea
Oliver D. Howes
Affiliation:
Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK Psychiatric Imaging, Medical Research Council Clinical Sciences Centre, Imperial College London, Hammersmith Hospital Campus, London, UK
Mattia Veronese
Affiliation:
Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK
Federico E. Turkheimer
Affiliation:
Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK
Yun-Sang Lee
Affiliation:
Department of Nuclear Medicine, College of Medicine, Seoul National University, Seoul, Republic of Korea
Jae Sung Lee
Affiliation:
Department of Nuclear Medicine, College of Medicine, Seoul National University, Seoul, Republic of Korea Department of Brain & Cognitive Sciences, College of Natural Sciences, Seoul National University, Seoul, Republic of Korea
Euitae Kim*
Affiliation:
Department of Neuropsychiatry, Seoul National University Bundang Hospital, Gyeonggi-do, Republic of Korea Department of Psychiatry, College of Medicine, Seoul National University, Seoul, Republic of Korea
Jun Soo Kwon
Affiliation:
Department of Brain & Cognitive Sciences, College of Natural Sciences, Seoul National University, Seoul, Republic of Korea Department of Psychiatry, College of Medicine, Seoul National University, Seoul, Republic of Korea
*
Author for correspondence: Euitae Kim, E-mail: [email protected]

Abstract

Background

Given that only a subgroup of patients with schizophrenia responds to first-line antipsychotic drugs, a key clinical question is what underlies treatment response. Observations that prefrontal activity correlates with striatal dopaminergic function, have led to the hypothesis that disrupted frontostriatal functional connectivity (FC) could be associated with altered dopaminergic function. Thus, the aim of this study was to investigate the relationship between frontostriatal FC and striatal dopamine synthesis capacity in patients with schizophrenia who had responded to first-line antipsychotic drug compared with those who had failed but responded to clozapine.

Methods

Twenty-four symptomatically stable patients with schizophrenia were recruited from Seoul National University Hospital, 12 of which responded to first-line antipsychotic drugs (first-line AP group) and 12 under clozapine (clozapine group), along with 12 matched healthy controls. All participants underwent resting-state functional magnetic resonance imaging and [18F]DOPA PET scans.

Results

No significant difference was found in the total PANSS score between the patient groups. Voxel-based analysis showed a significant correlation between frontal FC to the associative striatum and the influx rate constant of [18F]DOPA in the corresponding region in the first-line AP group. Region-of-interest analysis confirmed the result (control group: R2 = 0.019, p = 0.665; first-line AP group: R2 = 0.675, p < 0.001; clozapine group: R2 = 0.324, p = 0.054) and the correlation coefficients were significantly different between the groups.

Conclusions

The relationship between striatal dopamine synthesis capacity and frontostriatal FC is different between responders to first-line treatment and clozapine treatment in schizophrenia, indicating that a different pathophysiology could underlie schizophrenia in patients who respond to first-line treatments relative to those who do not.

Type
Original Articles
Copyright
Copyright © Cambridge University Press 2018 

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

Alexander, GE, DeLong, MR and Strick, PL (1986) Parallel organization of functionally segregated circuits linking basal ganglia and cortex. Annual Review of Neuroscience 9, 357381.Google Scholar
Andreasen, NC, Pressler, M, Nopoulos, P, Miller, D and Ho, BC (2010) Antipsychotic dose equivalents and dose-years: a standardized method for comparing exposure to different drugs. Biological Psychiatry 67, 255262.Google Scholar
Bai, YM, Ting Chen, T, Chen, JY, Chang, WH, Wu, B, Hung, CH and Kuo Lin, W (2007) Equivalent switching dose from oral risperidone to risperidone long-acting injection: a 48-week randomized, prospective, single-blind pharmacokinetic study. Journal of Clinical Psychiatry 68, 12181225.Google Scholar
Bloomfield, MA, Pepper, F, Egerton, A, Demjaha, A, Tomasi, G, Mouchlianitis, E, Maximen, L, Veronese, M, Turkheimer, F, Selvaraj, S and Howes, OD (2014) Dopamine function in cigarette smokers: an [(1)(8)F]-DOPA PET study. Neuropsychopharmacology 39, 23972404.Google Scholar
Brugger, SP and Howes, OD (2017) Heterogeneity and homogeneity of regional brain structure in schizophrenia: a meta-analysis. JAMA Psychiatry 74, 11041111.Google Scholar
Castellani, S and Adams, PM (1981) Effects of dopaminergic drugs on phencyclidine-induced behavior in the rat. Neuropharmacology 20, 371374.Google Scholar
Chao-Gan, Y and Yu-Feng, Z (2010) DPARSF: a MATLAB toolbox for “pipeline” data analysis of resting-state fMRI. Frontiers in Systems Neuroscience 4, 13.Google Scholar
Chumbley, JR and Friston, KJ (2009) False discovery rate revisited: FDR and topological inference using Gaussian random fields. NeuroImage 44, 6270.Google Scholar
Ciric, R, Wolf, DH, Power, JD, Roalf, DR, Baum, GL, Ruparel, K, Shinohara, RT, Elliott, MA, Eickhoff, SB, Davatzikos, C, Gur, RC, Gur, RE, Bassett, DS and Satterthwaite, TD (2017) Benchmarking of participant-level confound regression strategies for the control of motion artifact in studies of functional connectivity. NeuroImage 154, 174187.Google Scholar
Daskalakis, ZJ and George, TP (2009) Clozapine, GABA(B), and the treatment of resistant schizophrenia. Clinical Pharmacology and Therapeutics 86, 442446.Google Scholar
Demjaha, A, Murray, RM, McGuire, PK, Kapur, S and Howes, OD (2012) Dopamine synthesis capacity in patients with treatment-resistant schizophrenia. American Journal of Psychiatry 169, 12031210.Google Scholar
Demjaha, A, Lappin, JM, Stahl, D, Patel, MX, MacCabe, JH, Howes, OD, Heslin, M, Reininghaus, UA, Donoghue, K, Lomas, B, Charalambides, M, Onyejiaka, A, Fearon, P, Jones, P, Doody, G, Morgan, C, Dazzan, P and Murray, RM (2017) Antipsychotic treatment resistance in first-episode psychosis: prevalence, subtypes and predictors. Psychological Medicine 47, 19811989.Google Scholar
Eblen, F and Graybiel, AM (1995) Highly restricted origin of prefrontal cortical inputs to striosomes in the macaque monkey. Journal of Neuroscience 15, 59996013.Google Scholar
Egerton, A, Demjaha, A, McGuire, P, Mehta, MA and Howes, OD (2010) The test–retest reliability of 18F-DOPA PET in assessing striatal and extrastriatal presynaptic dopaminergic function. NeuroImage 50, 524531.Google Scholar
Eklund, A, Nichols, TE and Knutsson, H (2016) Cluster failure: why fMRI inferences for spatial extent have inflated false-positive rates. Proceedings of the National Academy of Sciences of the United States of America 113, 79007905.Google Scholar
Ellison-Wright, I and Bullmore, E (2009) Meta-analysis of diffusion tensor imaging studies in schizophrenia. Schizophrenia Research 108, 310.Google Scholar
Ferenczi, EA, Zalocusky, KA, Liston, C, Grosenick, L, Warden, MR, Amatya, D, Katovich, K, Mehta, H, Patenaude, B, Ramakrishnan, C, Kalanithi, P, Etkin, A, Knutson, B, Glover, GH and Deisseroth, K (2016) Prefrontal cortical regulation of brainwide circuit dynamics and reward-related behavior. Science 351, aac9698.Google Scholar
First, M, Spitzer, RL, Gibbon, M and Williams, J (2002) Structured clinical interview for DSM-IVTR axis I disorders, research version Patient Edition (SCID-I/P), Biometrics Research, New York State Psychiatric Institute, New York, NY.Google Scholar
Fischl, B (2012) Freesurfer. NeuroImage 62, 774781.Google Scholar
Fornito, A, Yucel, M, Patti, J, Wood, SJ and Pantelis, C (2009) Mapping grey matter reductions in schizophrenia: an anatomical likelihood estimation analysis of voxel-based morphometry studies. Schizophrenia Research 108, 104113.Google Scholar
Fornito, A, Harrison, BJ, Goodby, E, Dean, A, Ooi, C, Nathan, PJ, Lennox, BR, Jones, PB, Suckling, J and Bullmore, ET (2013) Functional dysconnectivity of corticostriatal circuitry as a risk phenotype for psychosis. JAMA Psychiatry 70, 11431151.Google Scholar
Friston, KJ (1999) Schizophrenia and the disconnection hypothesis. Acta Psychiatrica Scandinavica Supplementum 395, 6879.Google Scholar
Fusar-Poli, P, Howes, OD, Allen, P, Broome, M, Valli, I, Asselin, MC, Montgomery, AJ, Grasby, PM and McGuire, P (2011) Abnormal prefrontal activation directly related to pre-synaptic striatal dopamine dysfunction in people at clinical high risk for psychosis. Molecular Psychiatry 16, 6775.Google Scholar
Gillespie, AL, Samanaite, R, Mill, J, Egerton, A and MacCabe, JH (2017) Is treatment-resistant schizophrenia categorically distinct from treatment-responsive schizophrenia? A systematic review. BMC Psychiatry 17, 12.Google Scholar
Glahn, DC, Laird, AR, Ellison-Wright, I, Thelen, SM, Robinson, JL, Lancaster, JL, Bullmore, E and Fox, PT (2008) Meta-analysis of gray matter anomalies in schizophrenia: application of anatomic likelihood estimation and network analysis. Biological Psychiatry 64, 774781.Google Scholar
Gleich, T, Deserno, L, Lorenz, RC, Boehme, R, Pankow, A, Buchert, R, Kuhn, S, Heinz, A, Schlagenhauf, F and Gallinat, J (2015) Prefrontal and striatal glutamate differently relate to striatal dopamine: potential regulatory mechanisms of striatal presynaptic dopamine function? Journal of Neuroscience 35, 96159621.Google Scholar
Grunder, G, Vernaleken, I, Muller, MJ, Davids, E, Heydari, N, Buchholz, HG, Bartenstein, P, Munk, OL, Stoeter, P, Wong, DF, Gjedde, A and Cumming, P (2003) Subchronic haloperidol downregulates dopamine synthesis capacity in the brain of schizophrenic patients in vivo. Neuropsychopharmacology 28, 787794.Google Scholar
Haber, SN, Kim, KS, Mailly, P and Calzavara, R (2006) Reward-related cortical inputs define a large striatal region in primates that interface with associative cortical connections, providing a substrate for incentive-based learning. Journal of Neuroscience 26, 83688376.Google Scholar
Hammers, A, Allom, R, Koepp, MJ, Free, SL, Myers, R, Lemieux, L, Mitchell, TN, Brooks, DJ and Duncan, JS (2003) Three-dimensional maximum probability atlas of the human brain, with particular reference to the temporal lobe. Human Brain Mapping 19, 224247.Google Scholar
Horga, G, Cassidy, CM, Xu, X, Moore, H, Slifstein, M, Van Snellenberg, JX and Abi-Dargham, A (2016) Dopamine-related disruption of functional topography of striatal connections in unmedicated patients with schizophrenia. JAMA Psychiatry 73, 862870.Google Scholar
Howes, OD and Kapur, S (2014) A neurobiological hypothesis for the classification of schizophrenia: type A (hyperdopaminergic) and type B (normodopaminergic). The British Journal of Psychiatry 205, 13.Google Scholar
Howes, OD, Egerton, A, Allan, V, McGuire, P, Stokes, P and Kapur, S (2009 a) Mechanisms underlying psychosis and antipsychotic treatment response in schizophrenia: insights from PET and SPECT imaging. Current Pharmaceutical Design 15, 25502559.Google Scholar
Howes, OD, Montgomery, AJ, Asselin, MC, Murray, RM, Valli, I, Tabraham, P, Bramon-Bosch, E, Valmaggia, L, Johns, L, Broome, M, McGuire, PK and Grasby, PM (2009 b) Elevated striatal dopamine function linked to prodromal signs of schizophrenia. Archives of General Psychiatry 66, 1320.Google Scholar
Howes, OD, Bose, SK, Turkheimer, F, Valli, I, Egerton, A, Valmaggia, LR, Murray, RM and McGuire, P (2011) Dopamine synthesis capacity before onset of psychosis: a prospective [18F]-DOPA PET imaging study. American Journal of Psychiatry 168, 13111317.Google Scholar
Howes, O, McCutcheon, R and Stone, J (2015) Glutamate and dopamine in schizophrenia: an update for the 21st century. Journal of Psychopharmacology 29, 97115.Google Scholar
Howes, OD, McCutcheon, R, Agid, O, de Bartolomeis, A, van Beveren, NJ, Birnbaum, ML, Bloomfield, MA, Bressan, RA, Buchanan, RW, Carpenter, WT, Castle, DJ, Citrome, L, Daskalakis, ZJ, Davidson, M, Drake, RJ, Dursun, S, Ebdrup, BH, Elkis, H, Falkai, P, Fleischacker, WW, Gadelha, A, Gaughran, F, Glenthoj, BY, Graff-Guerrero, A, Hallak, JE, Honer, WG, Kennedy, J, Kinon, BJ, Lawrie, SM, Lee, J, Leweke, FM, MacCabe, JH, McNabb, CB, Meltzer, H, Moller, HJ, Nakajima, S, Pantelis, C, Reis Marques, T, Remington, G, Rossell, SL, Russell, BR, Siu, CO, Suzuki, T, Sommer, IE, Taylor, D, Thomas, N, Ucok, A, Umbricht, D, Walters, JT, Kane, J and Correll, CU (2017) Treatment-resistant schizophrenia: Treatment Response and Resistance in Psychosis (TRRIP) working group consensus guidelines on diagnosis and terminology. American Journal of Psychiatry 174, 216229.Google Scholar
Ito, H, Takano, H, Takahashi, H, Arakawa, R, Miyoshi, M, Kodaka, F, Okumura, M, Otsuka, T and Suhara, T (2009) Effects of the antipsychotic risperidone on dopamine synthesis in human brain measured by positron emission tomography with L-[beta-11C]DOPA: a stabilizing effect for dopaminergic neurotransmission? Journal of Neuroscience 29, 13730–4.Google Scholar
Ito, H, Takano, H, Arakawa, R, Takahashi, H, Kodaka, F, Takahata, K, Nogami, T, Suzuki, M and Suhara, T (2012) Effects of dopamine D2 receptor partial agonist antipsychotic aripiprazole on dopamine synthesis in human brain measured by PET with L-[beta-11C]DOPA. PLoS ONE 7, e46488.Google Scholar
Jaskiw, GE, Karoum, FK and Weinberger, DR (1990) Persistent elevations in dopamine and its metabolites in the nucleus accumbens after mild subchronic stress in rats with ibotenic acid lesions of the medial prefrontal cortex. Brain Research 534, 321323.Google Scholar
Jauhar, S, Veronese, M, Nour, MM, Rogdaki, M, Hathway, P, Turkheimer, FE, Stone, J, Egerton, A, McGuire, P, Kapur, S and Howes, OD (2018) Determinants of treatment response in first-episode psychosis: an (18)F-DOPA PET study. Molecular Psychiatry. Available online at https://doi.org/10.1038/s41380-018-0042-4 (accessed 1 May 2018).Google Scholar
Jenkinson, M, Bannister, P, Brady, M and Smith, S (2002) Improved optimization for the robust and accurate linear registration and motion correction of brain images. NeuroImage 17, 825841.Google Scholar
Joel, D and Weiner, I (2000) The connections of the dopaminergic system with the striatum in rats and primates: an analysis with respect to the functional and compartmental organization of the striatum. Neuroscience 96, 451474.Google Scholar
Kane, J, Honigfeld, G, Singer, J and Meltzer, H (1988) Clozapine for the treatment-resistant schizophrenic. A double-blind comparison with chlorpromazine. Archives of General Psychiatry 45, 789796.Google Scholar
Kegeles, LS, Abi-Dargham, A, Frankle, WG, Gil, R, Cooper, TB, Slifstein, M, Hwang, DR, Huang, Y, Haber, SN and Laruelle, M (2010) Increased synaptic dopamine function in associative regions of the striatum in schizophrenia. Archives of General Psychiatry 67, 231239.Google Scholar
Kim, E, Howes, OD, Veronese, M, Beck, K, Seo, S, Park, JW, Lee, JS, Lee, YS and Kwon, JS (2017) Presynaptic dopamine capacity in patients with treatment-resistant schizophrenia taking clozapine: an [(18)F]DOPA PET study. Neuropsychopharmacology 42, 941950.Google Scholar
Kraguljac, NV, White, DM, Hadley, JA, Visscher, K, Knight, D, ver Hoef, L, Falola, B and Lahti, AC (2016) Abnormalities in large scale functional networks in unmedicated patients with schizophrenia and effects of risperidone. Neuroimage Clinical 10, 146158.Google Scholar
Lally, J, Ajnakina, O, Di Forti, M, Trotta, A, Demjaha, A, Kolliakou, A, Mondelli, V, Reis Marques, T, Pariante, C, Dazzan, P, Shergil, SS, Howes, OD, David, AS, MacCabe, JH, Gaughran, F and Murray, RM (2016) Two distinct patterns of treatment resistance: clinical predictors of treatment resistance in first-episode schizophrenia spectrum psychoses. Psychological Medicine 46, 32313240.Google Scholar
Leucht, S, Kane, JM, Kissling, W, Hamann, J, Etschel, E and Engel, RR (2005) What does the PANSS mean? Schizophrenia Research 79, 231238.Google Scholar
Levine, SZ, Rabinowitz, J, Engel, R, Etschel, E and Leucht, S (2008) Extrapolation between measures of symptom severity and change: an examination of the PANSS and CGI. Schizophrenia Research 98, 318322.Google Scholar
Levitt, JJ, Nestor, PG, Levin, L, Pelavin, P, Lin, P, Kubicki, M, McCarley, RW, Shenton, ME and Rathi, Y (2017) Reduced structural connectivity in frontostriatal white matter tracts in the associative loop in schizophrenia. American Journal of Psychiatry 174, 11021111.Google Scholar
Lui, S, Li, T, Deng, W, Jiang, L, Wu, Q, Tang, H, Yue, Q, Huang, X, Chan, RC, Collier, DA, Meda, SA, Pearlson, G, Mechelli, A, Sweeney, JA and Gong, Q (2010) Short-term effects of antipsychotic treatment on cerebral function in drug-naive first-episode schizophrenia revealed by ‘resting state’ functional magnetic resonance imaging. Archives of General Psychiatry 67, 783792.Google Scholar
Martinez, D, Slifstein, M, Broft, A, Mawlawi, O, Hwang, DR, Huang, Y, Cooper, T, Kegeles, L, Zarahn, E, Abi-Dargham, A, Haber, SN and Laruelle, M (2003) Imaging human mesolimbic dopamine transmission with positron emission tomography. Part II: amphetamine-induced dopamine release in the functional subdivisions of the striatum. Journal of Cerebral Blood Flow and Metabolism 23, 285300.Google Scholar
McCutcheon, R, Beck, K, Jauhar, S and Howes, OD (2018) Defining the locus of dopaminergic dysfunction in schizophrenia: a meta-analysis and test of the mesolimbic hypothesis. Schizophrenia bulletin 44, 13011311.Google Scholar
McGowan, S, Lawrence, AD, Sales, T, Quested, D and Grasby, P (2004) Presynaptic dopaminergic dysfunction in schizophrenia: a positron emission tomographic [18F]fluorodopa study. Archives of General Psychiatry 61, 134142.Google Scholar
Meyer-Lindenberg, A, Miletich, RS, Kohn, PD, Esposito, G, Carson, RE, Quarantelli, M, Weinberger, DR and Berman, KF (2002) Reduced prefrontal activity predicts exaggerated striatal dopaminergic function in schizophrenia. Nature Neuroscience 5, 267271.Google Scholar
Minzenberg, MJ, Laird, AR, Thelen, S, Carter, CS and Glahn, DC (2009) Meta-analysis of 41 functional neuroimaging studies of executive function in schizophrenia. Archives of General Psychiatry 66, 811822.Google Scholar
Miyake, N, Thompson, J, Skinbjerg, M and Abi-Dargham, A (2011) Presynaptic dopamine in schizophrenia. CNS Neuroscience & Therapeutics 17, 104109.Google Scholar
Mizrahi, R, Addington, J, Rusjan, PM, Suridjan, I, Ng, A, Boileau, I, Pruessner, JC, Remington, G, Houle, S and Wilson, AA (2012) Increased stress-induced dopamine release in psychosis. Biological Psychiatry 71, 561567.Google Scholar
Mouchlianitis, E, McCutcheon, R and Howes, OD (2016) Brain-imaging studies of treatment-resistant schizophrenia: a systematic review. The Lancet. Psychiatry 3, 451463.Google Scholar
Paasonen, J, Salo, RA, Ihalainen, J, Leikas, JV, Savolainen, K, Lehtonen, M, Forsberg, MM and Grohn, O (2017) Dose–response effect of acute phencyclidine on functional connectivity and dopamine levels, and their association with schizophrenia-like symptom classes in rat. Neuropharmacology 119, 1525.Google Scholar
Parkes, L, Fulcher, B, Yucel, M and Fornito, A (2018) An evaluation of the efficacy, reliability, and sensitivity of motion correction strategies for resting-state functional MRI. NeuroImage 171, 415436.Google Scholar
Patlak, CS and Blasberg, RG (1985) Graphical evaluation of blood-to-brain transfer constants from multiple-time uptake data. Generalizations. Journal of Cerebral Blood Flow and Metabolism 5, 584590.Google Scholar
Pomarol-Clotet, E, Salvador, R, Sarro, S, Gomar, J, Vila, F, Martinez, A, Guerrero, A, Ortiz-Gil, J, Sans-Sansa, B, Capdevila, A, Cebamanos, JM and McKenna, PJ (2008) Failure to deactivate in the prefrontal cortex in schizophrenia: dysfunction of the default mode network? Psychological Medicine 38, 11851193.Google Scholar
Pomarol-Clotet, E, Canales-Rodriguez, EJ, Salvador, R, Sarro, S, Gomar, JJ, Vila, F, Ortiz-Gil, J, Iturria-Medina, Y, Capdevila, A and McKenna, PJ (2010) Medial prefrontal cortex pathology in schizophrenia as revealed by convergent findings from multimodal imaging. Molecular Psychiatry 15, 823830.Google Scholar
Sambataro, F, Blasi, G, Fazio, L, Caforio, G, Taurisano, P, Romano, R, Di Giorgio, A, Gelao, B, Lo Bianco, L, Papazacharias, A, Popolizio, T, Nardini, M and Bertolino, A (2009) Treatment with olanzapine is associated with modulation of the default mode network in patients with schizophrenia. Neuropsychopharmacology 35, 904.Google Scholar
Sarpal, DK, Robinson, DG, Lencz, T, Argyelan, M, Ikuta, T, Karlsgodt, K, Gallego, JA, Kane, JM, Szeszko, PR and Malhotra, AK (2015) Antipsychotic treatment and functional connectivity of the striatum in first-episode schizophrenia. JAMA Psychiatry 72, 513.Google Scholar
Sarpal, DK, Argyelan, M, Robinson, DG, Szeszko, PR, Karlsgodt, KH, John, M, Weissman, N, Gallego, JA, Kane, JM, Lencz, T and Malhotra, AK (2016) Baseline striatal functional connectivity as a predictor of response to antipsychotic drug treatment. American Journal of Psychiatry 173, 6977.Google Scholar
Satterthwaite, TD, Elliott, MA, Gerraty, RT, Ruparel, K, Loughead, J, Calkins, ME, Eickhoff, SB, Hakonarson, H, Gur, RC, Gur, RE and Wolf, DH (2013) An improved framework for confound regression and filtering for control of motion artifact in the preprocessing of resting-state functional connectivity data. NeuroImage 64, 240256.Google Scholar
Selvaraj, S, Turkheimer, F and Howes, O (2014) Dopamine transporter imaging: nonindependence of regional measures. Molecular Psychiatry 19, 964.Google Scholar
Shilliam, CS and Dawson, LA (2005) The effect of clozapine on extracellular dopamine levels in the shell subregion of the rat nucleus accumbens is reversed following chronic administration: comparison with a selective 5-HT(2C) receptor antagonist. Neuropsychopharmacology 30, 372380.Google Scholar
Simpson, EH, Kellendonk, C and Kandel, E (2010) A possible role for the striatum in the pathogenesis of the cognitive symptoms of schizophrenia. Neuron 65, 585596.Google Scholar
Siskind, D, McCartney, L, Goldschlager, R and Kisely, S (2016) Clozapine v. first- and second-generation antipsychotics in treatment-refractory schizophrenia: systematic review and meta-analysis. The British Journal of Psychiatry 209, 385392.Google Scholar
Turkheimer, FE, Brett, M, Visvikis, D and Cunningham, VJ (1999) Multiresolution analysis of emission tomography images in the wavelet domain. Journal of Cerebral Blood Flow and Metabolism 19, 11891208.Google Scholar
Tzourio-Mazoyer, N, Landeau, B, Papathanassiou, D, Crivello, F, Etard, O, Delcroix, N, Mazoyer, B and Joliot, M (2002) Automated anatomical labeling of activations in SPM using a macroscopic anatomical parcellation of the MNI MRI single-subject brain. NeuroImage 15, 273289.Google Scholar
van den Buuse, M (2010) Modeling the positive symptoms of schizophrenia in genetically modified mice: pharmacology and methodology aspects. Schizophrenia Bulletin 36, 246270.Google Scholar
Wahl, L, Chirakal, R, Firnau, G, Garnett, ES and Nahmias, C (1994) The distribution and kinetics of [18F]6-fluoro-3-O-methyl-L-dopa in the human brain. Journal of Cerebral Blood Flow and Metabolism 14, 664670.Google Scholar
White, TP, Wigton, R, Joyce, DW, Collier, T, Fornito, A and Shergill, SS (2016) Dysfunctional striatal systems in treatment-resistant schizophrenia. Neuropsychopharmacology 41, 12741285.Google Scholar
Whitfield-Gabrieli, S, Thermenos, HW, Milanovic, S, Tsuang, MT, Faraone, SV, McCarley, RW, Shenton, ME, Green, AI, Nieto-Castanon, A, LaViolette, P, Wojcik, J, Gabrieli, JD and Seidman, LJ (2009) Hyperactivity and hyperconnectivity of the default network in schizophrenia and in first-degree relatives of persons with schizophrenia. Proceedings of the National Academy of Sciences of the United States of America 106, 12791284.Google Scholar
Zhou, Y, Fan, L, Qiu, C and Jiang, T (2015) Prefrontal cortex and the dysconnectivity hypothesis of schizophrenia. Neuroscience Bulletin 31, 207219.Google Scholar