Original article| Volume 48, ISSUE 2, P99-109, July 15, 2000

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Schizophrenic subjects show aberrant fMRI activation of dorsolateral prefrontal cortex and basal ganglia during working memory performance


      Background: Working memory (WM) deficits in schizophrenia have been associated with dorsolateral prefrontal cortex (DLPFC) dysfunction in neuroimaging studies. We previously found increased DLPFC activation in schizophrenic versus normal subjects during WM performance (
      • Manoach D.S
      • Press D.Z
      • Thangaraj V
      • et al.
      Schizophrenic subjects activate dorsolateral prefrontal cortex during a working memory task as measured by fMRI.
      ). We now have investigated whether schizophrenic subjects recruit different brain regions, particularly the basal ganglia and thalamus, components of frontostriatal circuitry thought to mediate WM.
      Methods: We examined regional brain activation in nine normal and nine schizophrenic subjects during WM performance using functional magnetic resonance imaging. Subjects performed a modified version of the Sternberg Item Recognition Paradigm that included a monetary reward for correct responses. We compared high and low WM load conditions to each other and to a non-WM baseline condition. We examined activation in both individual subjects and averaged group data.
      Results: Relative to normal subjects, schizophrenic subjects exhibited deficient WM performance, at least an equal magnitude of right DLPFC activation, significantly greater left DLPFC activation, and increased spatial heterogeneity of DLPFC activation. Furthermore, only the schizophrenic group activated the basal ganglia and thalamus, even when matched for task performance with the normal group.
      Conclusions: Aberrant WM performance and brain activation in schizophrenia may reflect dysfunction of frontostriatal circuitry that subserves WM. Future studies will elucidate the contribution of the anatomical components of this circuitry to WM deficits.


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        • Alexander G.E
        • Delong M.R
        • Strick P.L
        Parallel organization of functionally segregated circuits linking basal ganglia and cortex.
        Annu Rev Neurosci. 1986; 9: 357-381
        • Apicella P
        • Scarnati E
        • Ljungberg T
        • Schultz W
        Neuronal activity in monkey striatum related to the expectation of predictable environmental events.
        J Neurophysiol. 1992; 68: 945-960
        • Baddeley A
        Working memory.
        Science. 1992; 255: 556-559
        • Barch D.M
        • Braver T.S
        • Nystrom L.E
        • et al.
        Dissociating working memory from task difficulty in human prefrontal cortex.
        Neuropsychologia. 1997; 35: 1373-1380
        • Battig K
        • Rosvold H.E
        • Mishkin M
        Comparison of the effect of frontal and caudate lesions on delayed response and alternation in monkeys.
        J Comp Physiol Psychol. 1960; 53: 400-404
        • Blair J.R
        • Spreen O
        Predicting premorbid IQ.
        Clin Neuropsychol. 1989; 3: 129-136
        • Braver T.S
        • Cohen J.D
        • Nystrom L.E
        • et al.
        A parametric study of prefrontal cortex involvement in human working memory.
        Neuroimage. 1997; 5: 49-62
        • Buchsbaum M.S
        • Haier R.J
        • Potkin S.G
        • et al.
        Frontostriatal disorder of cerebral metabolism in never-medicated schizophrenics.
        Arch Gen Psychiatry. 1992; 49: 935-942
        • Bush G
        • Whalen P.J
        • Rosen B.R
        • et al.
        The counting stroop.
        Hum Brain Mapping. 1998; 6: 270-282
        • Callicott J.H
        • Mattay V.S
        • Bertolino A
        • et al.
        Physiological characteristics of capacity constraints in working memory as revealed by functional MRI.
        Cereb Cortex. 1999; 9: 20-26
        • Callicott J.H
        • Ramsey N.F
        • Tallent K
        • et al.
        Functional magnetic resonance imaging brain mapping in psychiatry.
        Neuropsychopharmacology. 1998; 18: 186-196
        • Carter C
        • Robertson L
        • Nordahl T
        • et al.
        Spatial working memory deficits and their relationship to negative symptoms in unmedicated schizophrenia patients.
        Biol Psychiatry. 1996; 40: 930-932
        • Chakos M.H
        • Lieberman J.A
        • Bilder R.M
        • et al.
        Increase in caudate nuclei volumes of first-episode schizophrenic patients taking antipsychotic drugs.
        Am J Psychiatry. 1994; 151: 1430-1436
        • Cohen J.D
        • Perlstein W.M
        • Braver T.S
        • et al.
        Temporal dynamics of brain activation during a working memory task.
        Nature. 1997; 386: 604-608
        • D’Esposito M
        • Grossman M
        The physiological basis of executive function and working memory.
        Neuroscientist. 1996; 2: 345-352
        • Friedman H.R
        • Goldman-Rakic P.S
        Coactivation of prefrontal cortex and inferior parietal cortex in working memory tasks revealed by 2DG functional mapping in the rhesus monkey.
        J Neurosci. 1994; 14: 2775-2788
        • Frith C.D
        • Friston K.J
        • Herold S
        • et al.
        Regional brain activity in chronic schizophrenic patients during the performance of a verbal fluency task.
        Br J Psychiatry. 1995; 167: 343-349
        • Goldberg T.E
        • Berman K.F
        • Fleming K
        • et al.
        Uncoupling cognitive workload and prefrontal cortical physiology.
        Neuroimage. 1998; 7: 296-303
        • Goldberg T.E
        • Weinberger D.R
        Effects of neuroleptic medications on the cognition of patients with schizophrenia.
        J Clin Psychiatry. 1996; 57: 62-65
        • Hajnal J.V
        • Myers R
        • Oatridge A
        • et al.
        Artifacts due to stimulus correlated motion in functional imaging of the brain.
        Magn Reson Med. 1994; 31: 283-291
        • Hollingshead A.B
        Two Factor Index of Social Position. Yale University Press, New Haven, CT1965
      1. Holt JL, Van Horn JD, Esposito G, et al (1998, November): Variability in functional neuroanatomy in schizophrenia: Group vs. single-subject PET activation data. Abstract presented at the 28th annual meeting of the Society for Neuroscience, Los Angeles.

      2. Holt JL, Van Horn JD, Meyer-Lindenberg A, et al (1999, October): Multiple sources of signal abnormality underlying prefrontal hypofunction and increased variability in the sites of activation within BA 9/46 in individual medication free schizophrenic patients. Abstract presented at the 29th annual meeting of the Society for Neuroscience, Miami Beach, FL.

        • Houk J.C
        • Davis J.L
        • Beiser D.G
        Models of Information Processing in the Basal Ganglia. MIT Press, Cambridge, MA1995
        • Houk J.C
        • Wise S.P
        Distributed modular architectures linking basal ganglia, cerebellum, and cerebral cortex.
        Cereb Cortex. 1995; 5: 95-110
        • Jiang A
        • Kennedy D
        • Baker J
        • et al.
        Motion detection and correction in functional MR imaging.
        Hum Brain Mapping. 1995; 3: 1-12
        • Jonides J
        • Schumacher E.H
        • Smith E.E
        • et al.
        The role of parietal cortex in verbal working memory.
        J Neurosci. 1998; 18: 5026-5034
        • Jueptner M
        • Weiller C
        A review of differences between basal ganglia and cerebellar control of movements as revealed by functional imaging studies.
        Brain. 1998; 121: 1437-1449
        • Kay S.R
        • Fiszbein A
        • Opler L.A
        The positive and negative syndrome scale (PANSS) for schizophrenia.
        Schizophr Bull. 1987; 13: 261-276
      3. Knight RA, Manoach DS, Elliott DS, Hershenson M (in press): Perceptual organization in schizophrenia: the processing of symmetrical configurations. J Abnorm Psychol.

        • Levy R
        • Friedman H.R
        • Davachi L
        • Goldman-Rakic P.S
        Differential activation of the caudate nucleus in primates performing spatial and nonspatial working memory tasks.
        J Neurosci. 1997; 17: 3870-3882
      4. Manoach DS, Benson ES, Chang Y, et al (1999a, October): Test-retest reliability of a fMRI working memory paradigm in normal and schizophrenia subjects. Abstract presented at the 29th annual meeting of the Society for Neuroscience, Miami Beach, FL.

        • Manoach D.S
        • Press D.Z
        • Thangaraj V
        • et al.
        Schizophrenic subjects activate dorsolateral prefrontal cortex during a working memory task as measured by fMRI.
        Biol Psychiatry. 1999; 45: 1128-1137
        • Manoach D.S
        • Schlaug G
        • Siewert B
        • et al.
        Prefrontal cortex fMRI signal changes are correlated with working memory load.
        Neuroreport. 1997; 8: 545-549
        • Mattay V.S
        • Callicott J.H
        • Bertolino A
        • et al.
        Abnormal functional lateralization of the sensorimotor cortex in patients with schizophrenia.
        Neuroreport. 1997; 8: 2977-2984
        • Miller D.D
        • Rezai K
        • Alliger R
        • Andreasen N.C
        The effect of antipsychotic medication on relative cerebral blood perfusion in schizophrenia.
        Biol Psychiatry. 1997; 41: 550-559
      5. NIMH (1974): Abnormal Involuntary Movement Scale (AIMS), U.S. Public Health Service Publication No. MH-9-17. Washington, DC: U.S. Government Printing Office.

        • Overall J.E
        • Gorham D.R
        The brief psychiatric rating scale.
        Psychol Rep. 1962; 10: 799-812
        • Owen A.M
        • Iddon J.L
        • Hodges J.R
        • et al.
        Spatial and non-spatial working memory at different stages of Parkinson’s disease.
        Neuropsychologia. 1997; 35: 519-532
        • Park S
        • Holzman P.S
        Schizophrenics show spatial working memory deficits.
        Arch Gen Psychiatry. 1992; 49: 975-982
        • Park S
        • Puschel J
        • Sauter B.H
        • et al.
        Spatial working memory deficits and clinical symptoms in schizophrenia.
        Biol Psychiatry. 1999; 46: 392-400
        • Partiot A
        • Verin M
        • Pillon B
        • et al.
        Delayed response tasks in basal ganglia lesions in man.
        Neuropsychologia. 1996; 34: 709-721
        • Petrides M
        • Alivisatos B
        • Evans A.C
        • Meyer E
        Dissociation of human mid-dorsolateral from posterior dorsolateral frontal cortex in memory processing.
        Proc Natl Acad Sci U S A. 1993; 90: 873-877
        • Petrides M
        • Alivisatos B
        • Meyer E
        • Evans A.C
        Functional activation of the human prefrontal cortex during the performance of verbal working memory tasks.
        Proc Natl Acad Sci U S A. 1993; 90: 878-882
        • Rajkowska G
        • Goldman-Rakic P.S
        Cytoarchitectonic definition of prefrontal areas in the normal human cortex.
        Cereb Cortex. 1995; 5: 323-337
        • Rubin P
        • Holm S
        • Friberg L
        • et al.
        Altered modulation of prefrontal and subcortical brain activity in newly diagnosed schizophrenia and schizophreniform disorder.
        Arch Gen Psychiatry. 1991; 48: 987-995
        • Rypma B
        • Prabhakaran V
        • Desmond J.E
        • et al.
        Load-dependent roles of frontal brain regions in the maintenance of working memory.
        Neuroimage. 1999; 9: 216-226
        • Siegel B
        • Buchsbaum M
        • Bunney W
        • et al.
        Cortical-striatal-thalamic circuits and brain glucose metabolism activity in 70 unmedicated male schizophrenic patients.
        Am J Psychiatry. 1993; 150: 1325-1336
        • Silverstein S.M
        • Bakshi S
        • Chapman R.M
        • Nowlis G
        Perceptual organization of configural and nonconfigural effects of repeated exposure.
        Cogn Neuropsychiatry. 1998; 3: 209-223
        • Simpson G.M
        • Angus J.W.S
        A rating scale for extrapyramidal side effects.
        Acta Psychiatr Scand Suppl. 1970; 212: 11-19
        • Smith E.E
        • Jonides J
        • Marshuetz C
        • Koeppe R.A
        Components of verbal working memory.
        Proc Natl Acad Sci U S A. 1998; 95: 876-882
        • Spitzer R.L
        • Williams J.B
        • Gibbon M
        • First M.B
        The Structured Clinical Interview for DSM-III-R (SCID). I.
        Arch Gen Psychiatry. 1992; 49: 624-629
        • Sternberg S
        High-speed scanning in human memory.
        Science. 1966; 153: 652-654
        • Talairach J
        • Tournoux P
        Co-Planar Stereotaxic Atlas of the Human Brain. Thieme Medical Publishers, New York1988
        • Watanabe M
        Reward expectancy in primate prefrontal neurons.
        Nature. 1996; 382: 629-632
        • Weinberger D.R
        • Berman K.F
        Prefrontal function in schizophrenia.
        Philos Trans R Soc Lond B Biol Sci. 1996; 351: 1495-1503
        • White K
        • Ashton R
        Handedness assessment inventory.
        Neuropsychologia. 1976; 14: 261-264
        • Woods R.P
        • Cherry S.R
        • Mazziotta J.C
        Rapid automated algorithm for aligning and reslicing PET images.
        J Comput Assist Tomogr. 1992; 16: 620-633