Skip to main content
Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1996 Sep 3;93(18):9985–9990. doi: 10.1073/pnas.93.18.9985

Schizophrenia and cognitive dysmetria: a positron-emission tomography study of dysfunctional prefrontal-thalamic-cerebellar circuitry.

N C Andreasen 1, D S O'Leary 1, T Cizadlo 1, S Arndt 1, K Rezai 1, L L Ponto 1, G L Watkins 1, R D Hichwa 1
PMCID: PMC38542  PMID: 8790444

Abstract

Patients suffering from schizophrenia display subtle cognitive abnormalities that may reflect a difficulty in rapidly coordinating the steps that occur in a variety of mental activities. Working interactively with the prefrontal cortex, the cerebellum may play a role in coordinating both motor and cognitive performance. This positron-emission tomography study suggests the presence of a prefrontal-thalamic-cerebellar network that is activated when normal subjects recall complex narrative material, but is dysfunctional in schizophrenic patients when they perform the same task. These results support a role for the cerebellum in cognitive functions and suggest that patients with schizophrenia may suffer from a "cognitive dysmetria" due to dysfunctional prefrontal-thalamic-cerebellar circuitry.

Full text

PDF
9985

Images in this article

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Andreasen N. C., Arndt S., Swayze V., 2nd, Cizadlo T., Flaum M., O'Leary D., Ehrhardt J. C., Yuh W. T. Thalamic abnormalities in schizophrenia visualized through magnetic resonance image averaging. Science. 1994 Oct 14;266(5183):294–298. doi: 10.1126/science.7939669. [DOI] [PubMed] [Google Scholar]
  2. Andreasen N. C., Cizadlo T., Harris G., Swayze V., 2nd, O'Leary D. S., Cohen G., Ehrhardt J., Yuh W. T. Voxel processing techniques for the antemortem study of neuroanatomy and neuropathology using magnetic resonance imaging. J Neuropsychiatry Clin Neurosci. 1993 Spring;5(2):121–130. doi: 10.1176/jnp.5.2.121. [DOI] [PubMed] [Google Scholar]
  3. Andreasen N. C., Cohen G., Harris G., Cizadlo T., Parkkinen J., Rezai K., Swayze V. W., 2nd Image processing for the study of brain structure and function: problems and programs. J Neuropsychiatry Clin Neurosci. 1992 Spring;4(2):125–133. doi: 10.1176/jnp.4.2.125. [DOI] [PubMed] [Google Scholar]
  4. Andreasen N. C., O'Leary D. S., Arndt S., Cizadlo T., Hurtig R., Rezai K., Watkins G. L., Ponto L. L., Hichwa R. D. Short-term and long-term verbal memory: a positron emission tomography study. Proc Natl Acad Sci U S A. 1995 May 23;92(11):5111–5115. doi: 10.1073/pnas.92.11.5111. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Andreasen N. C., O'Leary D. S., Arndt S., Cizadlo T., Rezai K., Watkins G. L., Ponto L. L., Hichwa R. D. I. PET studies of memory: novel and practiced free recall of complex narratives. Neuroimage. 1995 Dec;2(4):284–295. doi: 10.1006/nimg.1995.1036. [DOI] [PubMed] [Google Scholar]
  6. Andreasen N. C. Pieces of the schizophrenia puzzle fall into place. Neuron. 1996 Apr;16(4):697–700. doi: 10.1016/s0896-6273(00)80090-2. [DOI] [PubMed] [Google Scholar]
  7. Andreasen N. C., Rezai K., Alliger R., Swayze V. W., 2nd, Flaum M., Kirchner P., Cohen G., O'Leary D. S. Hypofrontality in neuroleptic-naive patients and in patients with chronic schizophrenia. Assessment with xenon 133 single-photon emission computed tomography and the Tower of London. Arch Gen Psychiatry. 1992 Dec;49(12):943–958. doi: 10.1001/archpsyc.1992.01820120031006. [DOI] [PubMed] [Google Scholar]
  8. Andreasen N. C., Swayze V., O'Leary D. S., Nopoulos P., Cizadlo T., Harris G., Arndt S., Flaum M. Abnormalities in midline attentional circuitry in schizophrenia: evidence from magnetic resonance and positron emission tomography. Eur Neuropsychopharmacol. 1995;5 (Suppl):37–41. doi: 10.1016/0924-977x(95)00028-n. [DOI] [PubMed] [Google Scholar]
  9. Benes F. M., Vincent S. L., Alsterberg G., Bird E. D., SanGiovanni J. P. Increased GABAA receptor binding in superficial layers of cingulate cortex in schizophrenics. J Neurosci. 1992 Mar;12(3):924–929. doi: 10.1523/JNEUROSCI.12-03-00924.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Bogerts B. Recent advances in the neuropathology of schizophrenia. Schizophr Bull. 1993;19(2):431–445. doi: 10.1093/schbul/19.2.431. [DOI] [PubMed] [Google Scholar]
  11. Braff D. L. Information processing and attention dysfunctions in schizophrenia. Schizophr Bull. 1993;19(2):233–259. doi: 10.1093/schbul/19.2.233. [DOI] [PubMed] [Google Scholar]
  12. Buchsbaum M. S., Haier R. J., Potkin S. G., Nuechterlein K., Bracha H. S., Katz M., Lohr J., Wu J., Lottenberg S., Jerabek P. A. Frontostriatal disorder of cerebral metabolism in never-medicated schizophrenics. Arch Gen Psychiatry. 1992 Dec;49(12):935–942. doi: 10.1001/archpsyc.1992.01820120023005. [DOI] [PubMed] [Google Scholar]
  13. Buckner R. L., Petersen S. E., Ojemann J. G., Miezin F. M., Squire L. R., Raichle M. E. Functional anatomical studies of explicit and implicit memory retrieval tasks. J Neurosci. 1995 Jan;15(1 Pt 1):12–29. doi: 10.1523/JNEUROSCI.15-01-00012.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Carlsson M., Carlsson A. Schizophrenia: a subcortical neurotransmitter imbalance syndrome? Schizophr Bull. 1990;16(3):425–432. doi: 10.1093/schbul/16.3.425. [DOI] [PubMed] [Google Scholar]
  15. Dolan R. J., Fletcher P., Frith C. D., Friston K. J., Frackowiak R. S., Grasby P. M. Dopaminergic modulation of impaired cognitive activation in the anterior cingulate cortex in schizophrenia. Nature. 1995 Nov 9;378(6553):180–182. doi: 10.1038/378180a0. [DOI] [PubMed] [Google Scholar]
  16. Evans A. C., Beil C., Marrett S., Thompson C. J., Hakim A. Anatomical-functional correlation using an adjustable MRI-based region of interest atlas with positron emission tomography. J Cereb Blood Flow Metab. 1988 Aug;8(4):513–530. doi: 10.1038/jcbfm.1988.92. [DOI] [PubMed] [Google Scholar]
  17. Fletcher P. C., Frith C. D., Grasby P. M., Shallice T., Frackowiak R. S., Dolan R. J. Brain systems for encoding and retrieval of auditory-verbal memory. An in vivo study in humans. Brain. 1995 Apr;118(Pt 2):401–416. doi: 10.1093/brain/118.2.401. [DOI] [PubMed] [Google Scholar]
  18. Friston K. J., Frith C. D., Liddle P. F., Frackowiak R. S. Comparing functional (PET) images: the assessment of significant change. J Cereb Blood Flow Metab. 1991 Jul;11(4):690–699. doi: 10.1038/jcbfm.1991.122. [DOI] [PubMed] [Google Scholar]
  19. Frith C. D., Friston K. J., Herold S., Silbersweig D., Fletcher P., Cahill C., Dolan R. J., Frackowiak R. S., Liddle P. F. Regional brain activity in chronic schizophrenic patients during the performance of a verbal fluency task. Br J Psychiatry. 1995 Sep;167(3):343–349. doi: 10.1192/bjp.167.3.343. [DOI] [PubMed] [Google Scholar]
  20. Goldman-Rakic P. S. Working memory dysfunction in schizophrenia. J Neuropsychiatry Clin Neurosci. 1994 Fall;6(4):348–357. doi: 10.1176/jnp.6.4.348. [DOI] [PubMed] [Google Scholar]
  21. Grasby P. M., Frith C. D., Friston K. J., Bench C., Frackowiak R. S., Dolan R. J. Functional mapping of brain areas implicated in auditory--verbal memory function. Brain. 1993 Feb;116(Pt 1):1–20. doi: 10.1093/brain/116.1.1. [DOI] [PubMed] [Google Scholar]
  22. Gupta S., Andreasen N. C., Arndt S., Flaum M., Schultz S. K., Hubbard W. C., Smith M. Neurological soft signs in neuroleptic-naive and neuroleptic-treated schizophrenic patients and in normal comparison subjects. Am J Psychiatry. 1995 Feb;152(2):191–196. doi: 10.1176/ajp.152.2.191. [DOI] [PubMed] [Google Scholar]
  23. Haines D. E., Dietrichs E. An HRP study of hypothalamo-cerebellar and cerebello-hypothalamic connections in squirrel monkey (Saimiri sciureus). J Comp Neurol. 1984 Nov 10;229(4):559–575. doi: 10.1002/cne.902290409. [DOI] [PubMed] [Google Scholar]
  24. Holcomb H. H., Cascella N. G., Thaker G. K., Medoff D. R., Dannals R. F., Tamminga C. A. Functional sites of neuroleptic drug action in the human brain: PET/FDG studies with and without haloperidol. Am J Psychiatry. 1996 Jan;153(1):41–49. doi: 10.1176/ajp.153.1.41. [DOI] [PubMed] [Google Scholar]
  25. Holmes A. P., Blair R. C., Watson J. D., Ford I. Nonparametric analysis of statistic images from functional mapping experiments. J Cereb Blood Flow Metab. 1996 Jan;16(1):7–22. doi: 10.1097/00004647-199601000-00002. [DOI] [PubMed] [Google Scholar]
  26. Hurtig R. R., Hichwa R. D., O'Leary D. S., Boles Ponto L. L., Narayana S., Watkins G. L., Andreasen N. C. Effects of timing and duration of cognitive activation in [15O]water PET studies. J Cereb Blood Flow Metab. 1994 May;14(3):423–430. doi: 10.1038/jcbfm.1994.53. [DOI] [PubMed] [Google Scholar]
  27. Kapur S., Craik F. I., Jones C., Brown G. M., Houle S., Tulving E. Functional role of the prefrontal cortex in retrieval of memories: a PET study. Neuroreport. 1995 Oct 2;6(14):1880–1884. doi: 10.1097/00001756-199510020-00014. [DOI] [PubMed] [Google Scholar]
  28. Kapur S., Craik F. I., Tulving E., Wilson A. A., Houle S., Brown G. M. Neuroanatomical correlates of encoding in episodic memory: levels of processing effect. Proc Natl Acad Sci U S A. 1994 Mar 15;91(6):2008–2011. doi: 10.1073/pnas.91.6.2008. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Kim S. G., Uğurbil K., Strick P. L. Activation of a cerebellar output nucleus during cognitive processing. Science. 1994 Aug 12;265(5174):949–951. doi: 10.1126/science.8052851. [DOI] [PubMed] [Google Scholar]
  30. Leiner H. C., Leiner A. L., Dow R. S. Reappraising the cerebellum: what does the hindbrain contribute to the forebrain? Behav Neurosci. 1989 Oct;103(5):998–1008. doi: 10.1037//0735-7044.103.5.998. [DOI] [PubMed] [Google Scholar]
  31. Leiner H. C., Leiner A. L., Dow R. S. The human cerebro-cerebellar system: its computing, cognitive, and language skills. Behav Brain Res. 1991 Aug 29;44(2):113–128. doi: 10.1016/s0166-4328(05)80016-6. [DOI] [PubMed] [Google Scholar]
  32. Liddle P. F., Friston K. J., Frith C. D., Hirsch S. R., Jones T., Frackowiak R. S. Patterns of cerebral blood flow in schizophrenia. Br J Psychiatry. 1992 Feb;160:179–186. doi: 10.1192/bjp.160.2.179. [DOI] [PubMed] [Google Scholar]
  33. Middleton F. A., Strick P. L. Anatomical evidence for cerebellar and basal ganglia involvement in higher cognitive function. Science. 1994 Oct 21;266(5184):458–461. doi: 10.1126/science.7939688. [DOI] [PubMed] [Google Scholar]
  34. Pakkenberg B. Stereological quantitation of human brains from normal and schizophrenic individuals. Acta Neurol Scand Suppl. 1992;137:20–33. doi: 10.1111/j.1600-0404.1992.tb05034.x. [DOI] [PubMed] [Google Scholar]
  35. Passingham R. E. Changes in the size and organisation of the brain in man and his ancestors. Brain Behav Evol. 1975;11(2):73–90. doi: 10.1159/000123626. [DOI] [PubMed] [Google Scholar]
  36. Raichle M. E. Images of the mind: studies with modern imaging techniques. Annu Rev Psychol. 1994;45:333–356. doi: 10.1146/annurev.ps.45.020194.002001. [DOI] [PubMed] [Google Scholar]
  37. Schmahmann J. D. An emerging concept. The cerebellar contribution to higher function. Arch Neurol. 1991 Nov;48(11):1178–1187. doi: 10.1001/archneur.1991.00530230086029. [DOI] [PubMed] [Google Scholar]
  38. Shallice T., Fletcher P., Frith C. D., Grasby P., Frackowiak R. S., Dolan R. J. Brain regions associated with acquisition and retrieval of verbal episodic memory. Nature. 1994 Apr 14;368(6472):633–635. doi: 10.1038/368633a0. [DOI] [PubMed] [Google Scholar]
  39. Silbersweig D. A., Stern E., Frith C., Cahill C., Holmes A., Grootoonk S., Seaward J., McKenna P., Chua S. E., Schnorr L. A functional neuroanatomy of hallucinations in schizophrenia. Nature. 1995 Nov 9;378(6553):176–179. doi: 10.1038/378176a0. [DOI] [PubMed] [Google Scholar]
  40. Squire L. R., Zola-Morgan S. The medial temporal lobe memory system. Science. 1991 Sep 20;253(5026):1380–1386. doi: 10.1126/science.1896849. [DOI] [PubMed] [Google Scholar]
  41. Tulving E., Kapur S., Craik F. I., Moscovitch M., Houle S. Hemispheric encoding/retrieval asymmetry in episodic memory: positron emission tomography findings. Proc Natl Acad Sci U S A. 1994 Mar 15;91(6):2016–2020. doi: 10.1073/pnas.91.6.2016. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Tulving E., Kapur S., Markowitsch H. J., Craik F. I., Habib R., Houle S. Neuroanatomical correlates of retrieval in episodic memory: auditory sentence recognition. Proc Natl Acad Sci U S A. 1994 Mar 15;91(6):2012–2015. doi: 10.1073/pnas.91.6.2012. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Tulving E., Markowitsch H. J., Kapur S., Habib R., Houle S. Novelty encoding networks in the human brain: positron emission tomography data. Neuroreport. 1994 Dec 20;5(18):2525–2528. doi: 10.1097/00001756-199412000-00030. [DOI] [PubMed] [Google Scholar]
  44. Ungerleider L. G. Functional brain imaging studies of cortical mechanisms for memory. Science. 1995 Nov 3;270(5237):769–775. doi: 10.1126/science.270.5237.769. [DOI] [PubMed] [Google Scholar]
  45. Weinberger D. R., Berman K. F., Zec R. F. Physiologic dysfunction of dorsolateral prefrontal cortex in schizophrenia. I. Regional cerebral blood flow evidence. Arch Gen Psychiatry. 1986 Feb;43(2):114–124. doi: 10.1001/archpsyc.1986.01800020020004. [DOI] [PubMed] [Google Scholar]
  46. Worsley K. J., Evans A. C., Marrett S., Neelin P. A three-dimensional statistical analysis for CBF activation studies in human brain. J Cereb Blood Flow Metab. 1992 Nov;12(6):900–918. doi: 10.1038/jcbfm.1992.127. [DOI] [PubMed] [Google Scholar]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

RESOURCES