A Functional Magnetic Resonance Imaging Study of Working Memory Abnormalities in Schizophrenia


      Previous neuroimaging studies of working memory (WM) in schizophrenia, typically focusing on dorsolateral prefrontal cortex, yield conflicting results, possibly because of varied choice of tasks and analysis techniques. We examined neural function changes at several WM loads to derive a more complete picture of WM dysfunction in schizophrenia.


      We used a version of the Sternberg Item Recognition Paradigm to test WM function at five distinct loads. Eighteen schizophrenia patients and 18 matched healthy controls were scanned with functional magnetic resonance imaging at 3 Tesla.


      Patterns of both overactivation and underactivation in patients were observed depending on WM load. Patients’ activation was generally less responsive to load changes than control subjects’, and different patterns of between-group differences were observed for memory encoding and retrieval. In the specific case of successful retrieval, patients recruited additional neural circuits unused by control subjects. Behavioral effects were generally consistent with these imaging results.


      Differential findings of overactivation and underactivation may be attributable to patients’ decreased ability to focus and allocate neural resources at task-appropriate levels. Additionally, differences between encoding and retrieval suggest that WM dysfunction may be manifested differently during the distinct phases of encoding, maintenance, and retrieval.

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        • Baddeley A.
        Working memory.
        Science. 1992; 255: 556-559
        • Barch D.M.
        • Carter C.S.
        • Braver T.S.
        • Sabb F.W.
        • MacDonald A.3rd
        • Noll D.C.
        • et al.
        Selective deficits in prefrontal cortex function in medication-naive patients with schizophrenia.
        Arch Gen Psychiatry. 2001; 58: 280-288
        • Brett M.
        The MNI brain and the Talairach atlas. 2002; (Available at: Accessed March 1, 2005)
        • Callicott J.H.
        • Bertolino A.
        • Mattay V.S.
        • Langheim F.J.
        • Duyn J.
        • Coppola R.
        • et al.
        Physiological dysfunction of the dorsolateral prefrontal cortex in schizophrenia revisited.
        Cereb Cortex. 2000; 10: 1078-1092
        • Callicott J.H.
        • Mattay V.S.
        • Bertolino A.
        • Finn K.
        • Coppola R.
        • Frank J.A.
        • et al.
        Physiological characteristics of capacity constraints in working memory as revealed by functional MRI.
        Cerebral Cortex. 1999; 9: 20-26
        • Callicott J.H.
        • Mattay V.S.
        • Verchinski B.A.
        • Marenco S.
        • Egan M.F.
        • Weinberger D.R.
        Complexity of prefrontal cortical dysfunction in schizophrenia.
        Am J Psychiatry. 2003; 160: 2209-2215
        • Callicott J.H.
        • Ramsey N.F.
        • Tallent K.
        • Bertolino A.
        • Knable M.B.
        • Coppola R.
        • et al.
        Functional magnetic resonance imaging brain mapping in psychiatry.
        Neuropsychopharmacology. 1998; 18: 186-196
        • Cohen J.D.
        • Barch D.M.
        • Carter C.
        • Servan-Schreiber D.
        Context-processing deficits in schizophrenia.
        J Abnorm Psychol. 1999; 108: 120-133
        • Cohen J.D.
        • Braver T.S.
        • O’Reilly R.C.
        A computational approach to prefrontal cortex, cognitive control and schizophrenia.
        Philos Trans R Soc London B Biol Sci. 1996; 351: 1515-1527
        • D’Esposito M.
        • Postle B.R.
        • Ballard D.
        • Lease J.
        Maintenance versus manipulation of information held in working memory.
        Brain Cogn. 1999; 41: 66-86
        • First M.B.
        • Spitzer R.L.
        • Gibbon M.
        • Williams J.B.W.
        Structured Clinical Interview for DSM-IV-TR Axis I Disorders, Research Version, Patient Edition. (SCID-I/P). Biometrics Research, New York State Psychiatric Institute, New York2002
        • Ford J.M.
        • Gray M.
        • Whitfield S.L.
        • Turken A.U.
        • Glover G.
        • Faustman W.O.
        • et al.
        Acquiring and inhibiting prepotent responses in schizophrenia.
        Arch Gen Psychiatry. 2004; 61: 11-129
        • Freire L.
        • Mangin J.F.
        Motion correction algorithms may create spurious brain activations in the absence of subject motion.
        Neuroimage. 2001; 14: 709-722
        • Freire L.
        • Roche A.
        • Mangin J.F.
        What is the best similarity measure for motion correction in fMRI time series?.
        IEEE Trans Med Imaging. 2002; 21: 470-484
        • 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
        • Goldberg T.E.
        • Patterson K.J.
        • Taqqu Y.
        • Wilder K.
        Capacity limitations in short-term memory in schizophrenia.
        Psychol Med. 1998; 28: 665-673
        • Goldman-Rakic P.S.
        Prefrontal cortical dysfunction in schizophrenia.
        in: Carroll B.J. Barrett J.E. Psychopathology and the Brain. Raven Press, New York1991: 1-23
        • Henik A.
        • Carter C.S.
        • Salo R.
        • Chaderjian M.
        • Kraft L.
        • Nordahl T.E.
        • et al.
        Attentional control and word inhibition in schizophrenia.
        Psychiatry Res. 2002; 110: 137-149
        • Hollingshead A.B.
        Four Factor Index of Social Status. Department of Sociology, Yale University, New Haven, CT1975
        • Jaeggi S.M.
        • Seewer R.
        • Nirkko A.C.
        • Eckstein D.
        • Schroth G.
        • Groner R.
        • et al.
        Does excessive memory load attenuate activation in the prefrontal cortex? Load-dependent processing in single and dual tasks.
        Neuroimage. 2003; 19: 210-225
        • Jansma J.M.
        • Ramsey N.F.
        • Coppola R.
        • Kahn R.S.
        Specific versus nonspecific brain activity in a parametric N-back task.
        Neuroimage. 2000; 12: 688-697
        • Jansma J.M.
        • Ramsey N.F.
        • van der Wee N.J.
        • Kahn R.S.
        Working memory capacity in schizophrenia.
        Schizophr Res. 2004; 68: 159-171
        • Lancaster J.L.
        • Woldorff M.G.
        • Parsons L.M.
        • Liotti M.
        • Freitas C.S.
        • Rainey L.
        • et al.
        Automated Talairach Atlas labels for functional brain mapping.
        Hum Brain Mapp. 2000; 10: 120-131
        • Manoach D.S.
        Prefrontal cortex dysfunction during working memory performance in schizophrenia.
        Schizophr Res. 2003; 60: 285-298
        • Manoach D.S.
        • Gollub R.L.
        • Benson E.S.
        • Searl M.M.
        • Goff D.C.
        • Halpern E.
        • et al.
        Schizophrenic subjects show aberrant fMRI activation of dorsolateral prefrontal cortex and basal ganglia during working memory performance.
        Biol Psychiatry. 2000; 48: 99-109
        • Manoach D.S.
        • Greve D.N.
        • Lindgren K.A.
        • Dale A.M.
        Identifying regional activity associated with temporally separated components of working memory using event-related functional MRI.
        Neuroimage. 2003; 20: 1670-1684
        • Manoach D.S.
        • Press D.Z.
        • Thangaraj V.
        • Searl M.M.
        • Goff D.C.
        • Halpern E.
        • 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.
        • Darby D.
        • Bly B.M.
        • Benfield A.
        • et al.
        Prefrontal cortex fMRI signal changes are correlated with working memory load.
        NeuroReport. 1997; 8: 545-549
        • Menon V.
        • Anagnoson R.T.
        • Mathalon D.H.
        • Glover G.H.
        • Pfefferbaum A.
        Functional neuroanatomy of auditory working memory in schizophrenia.
        Neuroimage. 2001; 13: 433-446
        • Miller E.K.
        • Erickson C.A.
        • Desimone R.
        Neural mechanisms of visual working memory in prefrontal cortex of the macaque.
        J Neurosci. 1996; 16: 5154-5167
        • Miller G.A.
        The magical number 7, plus or minus 2—some limits on our capacity for processing information.
        Psychol Rev. 1956; 63: 81-97
        • Nelson H.E.
        The National Adult Reading Test (NART). NFER-Nelson, Windsor, UK1982
        • Oldfield R.
        The assessment and analyses of handedness.
        Neuropsychologia. 1971; 9: 97-113
        • 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.
        • Rentsch M.
        • Hell D.
        Spatial working memory deficits and clinical symptoms in schizophrenia.
        Biol Psychiatry. 1999; 46: 392-400
        • Perlstein W.M.
        • Carter C.S.
        • Noll D.C.
        • Cohen J.D.
        Relation of prefrontal cortex dysfunction to working memory and symptoms in schizophrenia.
        Am J Psychiatry. 2001; 158: 1105-1113
        • Petrides M.
        Impairments on nonspatial self-ordered and externally ordered working memory tasks after lesions of the mid-dorsal part of the lateral frontal cortex in the monkey.
        J Neurosci. 1995; 15: 359-375
        • Rypma B.
        • D’Esposito M.
        The roles of prefrontal brain regions in components of working memory.
        Proc Nat Acad Sci U S A. 1999; 96: 6558-6563
        • Servan-Schreiber D.
        • Cohen J.D.
        • Steingard S.
        Schizophrenic deficits in the processing of context. A test of a theoretical model.
        Arch Gen Psychiatry. 1996; 53: 1105-1112
        • 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, New York1988
        • Veltman D.J.
        • Rombouts S.A.
        • Dolan R.J.
        Maintenance versus manipulation in verbal working memory revisited.
        Neuroimage. 2003; 18: 247-256
        • 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; 43: 114-124
        • Wexler B.E.
        • Stevens A.A.
        • Bowers A.A.
        • Sernyak M.J.
        • Goldman-Rakic P.S.
        Word and tone working memory deficits in schizophrenia.
        Arch Gen Psychiatry. 1998; 55: 1093-1096
        • Yurgelun-Todd D.A.
        • Waternaux C.M.
        • Cohen B.M.
        • Gruber S.A.
        • English C.D.
        • Renshaw P.F.
        Functional magnetic resonance imaging of schizophrenic patients and comparison subjects during word production.
        Am J Psychiatry. 1996; 153: 200-205