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Cerebellar white-matter changes in cannabis users with and without schizophrenia

Published online by Cambridge University Press:  05 April 2011

N. Solowij*
Affiliation:
School of Psychology, University of Wollongong, Australia Schizophrenia Research Institute, Sydney, Australia
M. Yücel
Affiliation:
Melbourne Neuropsychiatry Centre, University of Melbourne, Australia Orygen Youth Health Research Centre, University of Melbourne, Australia
C. Respondek
Affiliation:
School of Psychology, University of Wollongong, Australia
S. Whittle
Affiliation:
Melbourne Neuropsychiatry Centre, University of Melbourne, Australia
E. Lindsay
Affiliation:
Melbourne Neuropsychiatry Centre, University of Melbourne, Australia
C. Pantelis
Affiliation:
Melbourne Neuropsychiatry Centre, University of Melbourne, Australia
D. I. Lubman
Affiliation:
Orygen Youth Health Research Centre, University of Melbourne, Australia Turning Point Alcohol and Drug Centre, Eastern Health and Monash University, Melbourne, Australia
*
*Address for correspondence: Dr N. Solowij, School of Psychology, University of Wollongong, Wollongong, NSW 2522, Australia. (Email: nadia@uow.edu.au)

Abstract

Background

The cerebellum is rich in cannabinoid receptors and implicated in the neuropathology of schizophrenia. Long-term cannabis use is associated with functional and structural brain changes similar to those evident in schizophrenia, yet its impact on cerebellar structure has not been determined. We examined cerebellar grey and white matter in cannabis users with and without schizophrenia.

Method

Seventeen patients with schizophrenia and 31 healthy controls were recruited; 48% of the healthy group and 47% of the patients were long-term heavy cannabis users (mean 19.7 and 17.9 years near daily use respectively). Cerebellar measures were extracted from structural 3-T magnetic resonance imaging (MRI) scans using semi-automated methods, and examined using analysis of covariance (ANCOVA) and correlational analyses.

Results

Cerebellar white-matter volume was reduced in cannabis users with and without schizophrenia compared to healthy non-users, by 29.7% and 23.9% respectively, and by 17.7% in patients without cannabis use. Healthy cannabis users did not differ in white-matter volume from either of the schizophrenia groups. There were no group differences in cerebellar grey matter or total volumes. Total cerebellar volume decreased as a function of duration of cannabis use in the healthy users. Psychotic symptoms and illness duration correlated with cerebellar measures differentially between patients with and without cannabis use.

Conclusions

Long-term heavy cannabis use in healthy individuals is associated with smaller cerebellar white-matter volume similar to that observed in schizophrenia. Reduced volumes were even more pronounced in patients with schizophrenia who use cannabis. Cannabis use may alter the course of brain maturational processes associated with schizophrenia.

Type
Original Articles
Copyright
Copyright © Cambridge University Press 2011

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References

Allin, M, Khan, O, Walshe, M, Kontis, D, Nosarti, C, Barker, G, Rifkin, L, Murray, RM (2009). Cannabis smoking and white matter in healthy volunteers. Schizophrenia Bulletin 35, 201.Google Scholar
Andersen, BB, Gundersen, HJG, Pakkenberg, B (2003). Aging of the human cerebellum: a stereological study. Journal of Comparative Neurology 466, 356365.CrossRefGoogle ScholarPubMed
Andreasen, NC (1983). The Scales for the Assessment of Positive (SAPS) and Negative (SANS) Symptoms. University of Iowa: Iowa City.Google Scholar
Andreasen, NC, Pierson, R (2008). The role of the cerebellum in schizophrenia. Biological Psychiatry 64, 8188.Google Scholar
Arnone, D, Barrick, TR, Chengappa, S, Mackay, CE, Clark, CA, Abou-Saleh, MT (2008). Corpus callosum damage in heavy marijuana use: preliminary evidence from diffusion tensor tractography and tract-based spatial statistics. NeuroImage 41, 10671074.Google Scholar
Ashtari, M, Cervellione, K, Cottone, J, Ardekani, BA, Kumra, S (2009). Diffusion abnormalities in adolescents and young adults with a history of heavy cannabis use. Journal of Psychiatric Research 43, 189204.Google Scholar
Ashton, JC, Appleton, I, Darlington, CL, Smith, PF (2004). Immunohistochemical localization of cannabinoid CB1 receptor in inhibitory interneurons in the cerebellum. Cerebellum 3, 222226.CrossRefGoogle ScholarPubMed
Bangalore, SS, Prasad, KM, Montrose, DM, Goradia, DD, Diwadkar, VA, Keshavan, MS (2008). Cannabis use and brain structural alterations in first episode schizophrenia – a region of interest, voxel based morphometric study. Schizophrenia Research 99, 16.Google Scholar
Berghuis, P, Rajnicek, A, Morozov, YM, Ross, R, Mulder, J, Urbán, G, Monory, K, Marsicano, G, Matteoli, M, Canty, A, Irving, A, Katona, I, Yanagawa, Y, Rakic, P, Lutz, B, Mackie, K, Harkany, T (2007). Hardwiring the brain: endocannabinoids shape neuronal connectivity. Science 316, 12121216.Google Scholar
Borgwardt, SJ, McGuire, PK, Aston, J, Gschwandtner, U, Pfluger, MO, Stieglitz, RD, Radue, EW, Riecher-Rossler, A (2008). Reductions in frontal, temporal and parietal volume associated with the onset of psychosis. Schizophrenia Research 106, 108114.Google Scholar
Charalambides, MA, Lappin, JM, Morgan, KD, Morgan, C, Fearon, P, Okon-Rocha, E, Jones, PB, Murray, RM, Dazzan, P (2009). Is there room for the ‘little brain’ in psychosis? An MRI study examining cerebellar volume and neurological function in first episode psychosis. Schizophrenia Bulletin 35, 205206.Google Scholar
Davis, KL, Stewart, DG, Friedman, JI, Buchsbaum, M, Harvey, PD, Hof, PR, Buxbaum, J, Haroutunian, V (2003). White matter changes in schizophrenia: evidence for myelin-related dysfunction. Archives of General Psychiatry 60, 443456.CrossRefGoogle ScholarPubMed
Free, SL, Bergin, PS, Fish, DR, Cook, MJ, Shorvon, SD, Stevens, JM (1995). Methods for normalization of hippocampal volumes measured with MR. American Journal of Neuroradiology 16, 637643.Google Scholar
Fride, E (2008). Multiple roles for the endocannabinoid system during the earliest stages of life: pre- and postnatal development. Journal of Neuroendocrinology 20, 7581.Google Scholar
Grigorenko, E, Kittler, J, Clayton, C, Wallace, D, Zhuang, SY, Bridges, D, Bundey, S, Boon, A, Pagget, C, Hayashizaki, S, Lowe, G, Hampson, R, Deadwyler, S (2002). Assessment of cannabinoid induced gene changes: tolerance and neuroprotection. Chemistry and Physics of Lipids 121, 257266.CrossRefGoogle ScholarPubMed
Hakak, Y, Walker, JR, Li, C, Wong, WH, Davis, KL, Buxbaum, JD, Haroutunian, V, Fienberg, AA (2001). Genome-wide expression analysis reveals dysregulation of myelination-related genes in chronic schizophrenia. Proceedings of the National Academy of Sciences USA, 98, 47464751.Google Scholar
Ho, BC, Mola, C, Andreasen, NC (2004). Cerebellar dysfunction in neuroleptic naive schizophrenia patients: clinical, cognitive, and neuroanatomic correlates of cerebellar neurologic signs. Biological Psychiatry 55, 11461153.Google Scholar
Huestegge, L, Radach, R, Kunert, HJ (2009). Long-term effects of cannabis on oculomotor function in humans. Journal of Psychopharmacology 23, 714722.Google Scholar
Ichimiya, T, Okubo, Y, Suhara, T, Sudo, Y (2001). Reduced volume of the cerebellar vermis in neuroleptic-naïve schizophrenia. Biological Psychiatry 49, 2027.Google Scholar
Karlsgodt, KH, Niendam, TA, Bearden, CE, Cannon, TD (2009). White matter integrity and prediction of social and role functioning in subjects at ultra-high risk for psychosis. Biological Psychiatry 66, 562569.CrossRefGoogle ScholarPubMed
Levitt, J, McCarley, R, Nestor, P, Petrescu, C, Donnino, R, Hirayasu, Y, Kikinis, R, Jolesz, F, Shenton, M (1999). Quantitative volumetric MRI study of the cerebellum and vermis in schizophrenia: clinical and cognitive correlates. American Journal of Psychiatry 156, 11051107.Google Scholar
Loeber, RT, Cintron, CMB, Yurgelun-Todd, DA (2001). Morphometry of individual cerebellar lobules in schizophrenia. American Journal of Psychiatry 158, 952954.Google Scholar
Lubman, DI, Yücel, M, Hall, WD (2007). Substance use and the adolescent brain: a toxic combination? Journal of Psychopharmacology 21, 792794.Google Scholar
Medina, KL, Nagel, BJ, Park, A, McQueeny, T, Tapert, SF (2007). Depressive symptoms in adolescents: associations with white matter volume and marijuana use. Journal of Child Psychology and Psychiatry 48, 592600.Google Scholar
Medina, KL, Nagel, BJ, Tapert, SF (2010). Abnormal cerebellar morphometry in abstinent adolescent marijuana users. Psychiatry Research: Neuroimaging 182, 152159.Google Scholar
Molina-Holgado, F, Pinteaux, E, Moore, JD, Molina-Holgado, E, Guaza, C, Gibson, FL, Rothwell, NJ (2003). Endogenous interleukin-1 receptor antagonist mediates anti-inflammatory and neuroprotective actions of cannabinoids in neurons and glia. Journal of Neuroscience 23, 64706474.Google Scholar
Monnet-Tschudi, F, Hazekamp, A, Perret, N, Zurich, M-G, Mangin, P, Giroud, C, Honegger, P (2008). Delta-9-tetrahydrocannabinol accumulation, metabolism and cell-type-specific adverse effects in aggregating brain cell cultures. Toxicology and Applied Pharmacology 228, 8–16.Google Scholar
Okugawa, G, Nobuhara, K, Takase, K, Kinoshita, T (2007). Cerebellar posterior superior vermis and cognitive cluster scores in drug-naive patients with first-episode schizophrenia. Neuropsychobiology 56, 216219.Google Scholar
O'Leary, DS, Block, RI, Turner, BM, Koeppel, J, Magnotta, VA, Boles Ponto, L, Watkins, GL, Hichwa, RD, Andreasen, NC (2003). Marijuana alters the human cerebellar clock. Neuroreport 14, 11451151.Google Scholar
Pantelis, C, Velakoulis, D, McGorry, PD, Wood, SJ, Suckling, J, Phillips, LJ, Yung, AR, Bullmore, ET, Brewer, W, Soulsby, B, Desmond, P, McGuire, PK (2003). Neuroanatomical abnormalities before and after onset of psychosis: a cross-sectional and longitudinal MRI study. Lancet 361, 281288.CrossRefGoogle Scholar
Parker, J, Mitchell, A, Kalpakidou, A, Walshe, M, Jung, HY, Nosarti, C, Santosh, P, Rifkin, L, Wyatt, J, Murray, RM, Allin, M (2008). Cerebellar growth and behavioural neuropsychological outcome in preterm adolescents. Brain 131, 13441351.Google Scholar
Picard, H, Amado, I, Mouchet-Mages, S, Olie, JP, Krebs, MO (2008). The role of the cerebellum in schizophrenia: an update of clinical, cognitive, and functional evidences. Schizophrenia Bulletin 34, 155172.Google Scholar
Pieperhoff, P, Hömke, L, Schneider, F, Habel, U, Shah, NJ, Zilles, K, Amunts, K (2008). Deformation field morphometry reveals age-related structural differences between the brains of adults up to 51 years. Journal of Neuroscience 28, 828842.Google Scholar
Premkumar, P, Fannon, D, Kuipers, E, Cooke, MA, Simmons, A, Kumari, V (2008). Association between a longer duration of illness, age and lower frontal lobe grey matter volume in schizophrenia. Behavioural Brain Research 193, 132139.Google Scholar
Rais, M, Cahn, W, Van Haren, N, Schnack, H, Caspers, E, Hulshoff Pol, H, Kahn, R (2008). Excessive brain volume loss over time in cannabis-using first-episode schizophrenia patients. American Journal of Psychiatry 165, 490496.Google Scholar
Schmahmann, JD (1991). An emerging concept: the cerebellar contribution to higher function. Archives of Neurology 48, 11781187.Google Scholar
Skosnik, PD, Edwards, CR, O'Donnell, BF, Steffen, A, Steinmetz, JE, Hetrick, WP (2008). Cannabis use disrupts eyeblink conditioning: evidence for cannabinoid modulation of cerebellar-dependent learning. Neuropsychopharmacology 33, 14321440.Google Scholar
Solowij, N, Michie, PT (2007). Cannabis and cognitive dysfunction: parallels with endophenotypes of schizophrenia? Journal of Psychiatry and Neuroscience 32, 3052.Google Scholar
Szeszko, PR, Robinson, DG, Sevy, S, Kumra, S, Rupp, CI, Betensky, JD, Lencz, T, Ashtari, M, Kane, JM, Malhotra, AK, Gunduz-Bruce, H, Napolitano, B, Bilder, RM (2007). Anterior cingulate grey-matter deficits and cannabis use in first-episode schizophrenia. British Journal of Psychiatry 190, 230236.Google Scholar
Tkachev, D, Mimmack, ML, Ryan, MM, Wayland, M, Freeman, T, Jones, PB, Starkey, M, Webster, MJ, Yolken, RH, Bahn, S (2003). Oligodendrocyte dysfunction in schizophrenia and bipolar disorder. Lancet 362, 798805.CrossRefGoogle ScholarPubMed
Velakoulis, D, Wood, SJ, Wong, MTH, McGorry, PD, Yung, A, Phillips, L, Brewer, W, Proffitt, T, Desmond, P, Pantelis, C (2006). Hippocampal and amygdala volumes differ according to psychosis stage and diagnosis: an MRI study of chronic schizophrenia, first-episode psychosis and ultra-high risk subjects. Archives of General Psychiatry 63, 139149.CrossRefGoogle Scholar
Walterfang, M, McGuire, PK, Yung, AR, Phillips, LJ, Velakoulis, D, Wood, SJ, Suckling, J, Bullmore, ET, Brewer, W, Soulsby, B, Desmond, P, McGorry, PD, Pantelis, C (2008). White matter volume changes in people who develop psychosis. British Journal of Psychiatry 193, 210215.Google Scholar
Ward, PB, Solowij, N, Peters, R, Otton, J, Chesher, G, Grenyer, B (2002). An MRI study of regional brain volumes in long-term cannabis users. Journal of Psychopharmacology 16, A56.Google Scholar
Wexler, BE, Zhu, H, Bell, MD, Nicholls, SS, Fulbright, RK, Gore, JC, Colibazzi, T, Amat, J, Bansal, R, Peterson, BS (2009). Neuropsychological near normality and brain structure abnormality in schizophrenia. American Journal of Psychiatry 166, 189195.Google Scholar
Whalley, HC, Gountouna, VE, Hall, J, McIntosh, A, Whyte, MC, Simonotto, E, Job, DE, Owens, DG, Johnstone, EC, Lawrie, SM (2007). Correlations between fMRI activation and individual psychotic symptoms in un-medicated subjects at high genetic risk of schizophrenia. BMC Psychiatry 7, 61.Google Scholar
Wright, IC, Rabe-Hesketh, S, Woodruff, PW, David, AS, Murray, RM, Bullmore, ET (2000). Metaanalysis of regional brain volumes in schizophrenia. American Journal of Psychiatry 157, 1625.Google Scholar
Yücel, M, Solowij, N, Respondek, C, Whittle, S, Fornito, A, Pantelis, C, Lubman, DI (2008). Regional brain abnormalities associated with long-term heavy cannabis use. Archives of General Psychiatry 65, 694701.Google Scholar
Yücel, M, Stuart, GW, Maruff, P, Velakoulis, D, Crowe, SF, Savage, G, Pantelis, C (2001). Hemispheric and gender-related differences in the gross morphology of the anterior cingulate/paracingulate cortex in normal volunteers: an MRI morphometric study. Cerebral Cortex 11, 1725.Google Scholar
Zhang, YY, Brady, M, Smith, S (2001). Segmentation of brain MR images through a hidden Markov random field model and the expectation-maximization algorithm. IEEE Transactions on Medical Imaging 20, 4557.Google Scholar