Mechanisms of Working Memory Impairment in Schizophrenia

Published:February 23, 2016DOI:



      The neural correlates of working memory (WM) impairment in schizophrenia remain a key puzzle in understanding the cognitive deficits and dysfunction of dorsolateral prefrontal cortex observed in this disorder. We sought to determine whether patients with schizophrenia exhibit an alteration in the inverted-U relationship between WM load and activation that we recently observed in healthy individuals and whether this could account for WM deficits in this population.


      Medicated (n = 30) and unmedicated (n = 21) patients with schizophrenia and healthy control subjects (n = 45) performed the self-ordered WM task during functional magnetic resonance imaging. We identified regions exhibiting an altered fit to an inverted-U relationship between WM load and activation that were also predictive of WM performance.


      A blunted inverted-U response was observed in left dorsolateral prefrontal cortex in patients and was associated with behavioral deficits in WM capacity. In addition, suppression of medial prefrontal cortex during WM was reduced in patients and was associated with poorer WM capacity in patients. Finally, activation of visual cortex in the cuneus was elevated in patients and associated with improved WM capacity. Together, these findings explained 55% of the interindividual variance in WM capacity when combined with diagnostic and medication status, which alone accounted for only 22% of the variance in WM capacity.


      These findings identify a novel biomarker and putative mechanism of WM deficits in patients with schizophrenia, a reduction or flattening of the inverted-U relationship between activation and WM load observed in healthy individuals in left dorsolateral prefrontal cortex.


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        • Lee J.
        • Park S.
        Working memory impairments in schizophrenia: A meta-analysis.
        J Abnorm Psychol. 2005; 114: 599-611
        • Green M.F.
        What are the functional consequences of neurocognitive deficits in schizophrenia?.
        Am J Psychiatry. 1996; 153: 321-330
        • Green M.F.
        Schizophrenia From a Neurocognitive Perspective: Probing the Impenetrable Darkness.
        Allyn & Bacon, Boston, MA1998
        • Slifstein M.
        • van de Geissen E.
        • Van Snellenberg J.
        • Thompson J.L.
        • Narendran R.
        • Gil R.
        • et al.
        Deficits in prefrontal cortical and extra-striatal dopamine release in schizophrenia: A positron emission tomographic functional magnetic resonance imaging study.
        JAMA Psychiatry. 2015; 72: 316-324
        • Abi-Dargham A.
        • Mawlawi O.
        • Lombardo I.
        • Gil R.
        • Martinez D.
        • Huang Y.
        • et al.
        Prefrontal dopamine D1 receptors and working memory in schizophrenia.
        J Neurosci. 2002; 22: 3708-3719
        • Cools R.
        • D’Esposito M.
        Inverted-U-shaped dopamine actions on human working memory and cognitive control.
        Biol Psychiatry. 2011; 69: e113-e125
        • Egan M.F.
        • Goldberg T.E.
        • Kolachana B.S.
        • Callicott J.H.
        • Mazzanti C.M.
        • Straub R.E.
        • et al.
        Effect of COMT Val108/158 Met genotype on frontal lobe function and risk for schizophrenia.
        Proc Natl Acad Sci U S A. 2001; 98: 6917-6922
        • Arnsten A.F.
        • Wang M.J.
        • Paspalas C.D.
        Neuromodulation of thought: Flexibilities and vulnerabilities in prefrontal cortical network synapses.
        Neuron. 2012; 76: 223-239
        • Abi-Dargham A.
        • Gil R.
        • Krystal J.
        • Baldwin R.M.
        • Seibyl J.P.
        • Bowers M.
        • et al.
        Increased striatal dopamine transmission in schizophrenia: Confirmation in a second cohort.
        Am J Psychiatry. 1998; 155: 761-767
        • Kegeles L.S.
        • Abi-Dargham A.
        • Frankle W.G.
        • Gil R.
        • Cooper T.B.
        • Slifstein M.
        • et al.
        Increased synaptic dopamine function in associative regions of the striatum in schizophrenia.
        Arch Gen Psychiatry. 2010; 67: 231-239
        • Laruelle M.
        • Abi-Dargham A.
        • van Dyck C.H.
        • Gil R.
        • D’Souza C.D.
        • Erdos J.
        • et al.
        Single photon emission computerized tomography imaging of amphetamine-induced dopamine release in drug-free schizophrenic subjects.
        Proc Natl Acad Sci U S A. 1996; 93: 9235-9240
        • Goff D.C.
        • Coyle J.T.
        The emerging role of glutamate in the pathophysiology and treatment of schizophrenia.
        Am J Psychiatry. 2001; 158: 1367-1377
        • Javitt D.C.
        Glutamate and schizophrenia: phencyclidine, N-methyl-D-aspartate receptors, and dopamine-glutamate interactions.
        Int Rev Neurobiol. 2007; 78: 69-108
        • Gonzalez-Burgos G.
        • Lewis D.A.
        GABA neurons and the mechanisms of network oscillations: Implications for understanding cortical dysfunction in schizophrenia.
        Schizophr Bull. 2008; 34: 944-961
        • Hashimoto T.
        • Volk D.W.
        • Eggan S.M.
        • Mirnics K.
        • Pierri J.N.
        • Sun Z.
        • et al.
        Gene expression deficits in a subclass of GABA neurons in the prefrontal cortex of subjects with schizophrenia.
        J Neurosci. 2003; 23: 6315-6326
        • Callicott J.H.
        • Ramsey N.F.
        • Tallen K.
        • Bertolino A.
        • Knable M.B.
        • Coppola R.
        • et al.
        Functional magnetic resonance imaging brain mapping in psychiatry: Methodological issues illustrated in a study of working memory in schizophrenia.
        Neuropsychopharmacology. 1998; 18: 186-196
        • Carter C.S.
        • Perlstein W.
        • Ganguli R.
        • Brar J.
        • Mintun M.
        • Cohen J.D.
        Functional hypofrontality and working memory dysfunction in schizophrenia.
        Am J Psychiatry. 1998; 155: 1285-1287
        • Stevens A.A.
        • Goldman-Rakic P.S.
        • Gore J.C.
        • Fulbright R.K.
        • Wexler B.E.
        Cortical dysfunction in schizophrenia during auditory word and tone working memory demonstrated by functional magnetic resonance imaging.
        Arch Gen Psychiatry. 1998; 55: 1097-1103
        • 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
        • Sawaguchi T.
        • Goldman-Rakic P.S.
        D1 dopamine receptors in prefrontal cortex: Involvement in working memory.
        Science. 1991; 251: 947-950
        • Williams G.V.
        • Goldman-Rakic P.S.
        Modulation of memory fields by dopamine D1 receptors in prefrontal cortex.
        Nature. 1995; 376: 572-575
        • 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.
        Cerebral Cortex. 2000; 10: 1078-1092
        • 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.
        • 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
        • Van Snellenberg J.X.
        • Torres I.J.
        • Thornton A.E.
        Functional neuroimaging of working memory in schizophrenia: Task performance as a moderating variable.
        Neuropsychology. 2006; 20: 497-510
        • Manoach D.S.
        Functional neuroimaging investigations of working memory deficits in schizophrenia: Reconciling discrepant findings.
        in: Lenzenweger M.F. Hooley J.M. Principles of Experimental Psychopathology: Essays in Honor of Brendan A Maher. American Psychological Association, Washington, DC2002: 119-134
        • Manoach D.S.
        Prefrontal cortex dysfunction during working memory performance in schizophrenia: Reconciling discrepant findings.
        Schizophr Res. 2003; 60: 285-298
        • Callicott J.H.
        • Mattay V.S.
        • Verchinski B.A.
        • Marenco S.
        • Egan M.F.
        • Weinberger D.R.
        Complexity of prefrontal cortical dysfunction in schizophrenia: More than up or down.
        Am J Psychiatry. 2003; 160: 2209-2215
        • Jansma J.M.
        • Ramsey N.F.
        • van der Wee N.J.
        • Kahn R.S.
        Working memory capacity in schizophrenia: A parametric fMRI study.
        Schizophr Res. 2004; 68: 159-171
        • Johnson M.R.
        • Morris N.A.
        • Astur R.S.
        • Calhoun V.D.
        • Mathalon D.H.
        • Kiehl K.A.
        • et al.
        A functional magnetic resonance imaging study of working memory abnormalities in schizophrenia.
        Biol Psychiatry. 2006; 60: 11-21
        • Karlsgodt K.H.
        • Glahn D.C.
        • van Erp T.G.M.
        • Therman S.
        • Huttunen M.
        • Manninen M.
        • et al.
        The relationship between performance and fMRI signal during working memory in patients with schizophrenia, unaffected co-twins, and control subjects.
        Schizophr Res. 2007; 89: 191-197
        • Potkin S.G.
        • Turner J.A.
        • Brown G.G.
        • McCarthy G.
        • Greve D.N.
        • Glover G.H.
        • et al.
        Working memory and DLPFC inefficiency in schizophrenia: The FBIRN study.
        Schizophr Bull. 2009; 35: 19-31
        • Schneider F.
        • Habel U.
        • Reske M.
        • Kellermann T.
        • Stocker T.
        • Shah N.J.
        • et al.
        Neural correlates of working memory dysfunction in first-episode schizophrenia patients: An fMRI multi-center study.
        Schizophr Res. 2007; 89: 198-210
        • Petrides M.
        • Milner B.
        Deficits on subject-ordered tasks after frontal- and temporal-lobe lesions in man.
        Neuropsychologia. 1982; 20: 249-262
        • Van Snellenberg J.X.
        • Conway A.R.
        • Spicer J.
        • Read C.
        • Smith E.E.
        Capacity estimates in working memory: Reliability and interrelationships among tasks.
        Cogn Affect Behav Neurosci. 2014; 14: 106-116
        • Van Snellenberg J.X.
        • Slifstein M.
        • Read C.
        • Weber J.
        • Thompson J.L.
        • Wager T.D.
        • et al.
        Dynamic shifts in brain network activation during supracapacity working memory task performance.
        Hum Brain Mapp. 2015; 36: 1245-1264
        • Karlsgodt K.H.
        • Sanz J.
        • van Erp T.G.
        • Bearden C.E.
        • Nuechterlein K.H.
        • Cannon T.D.
        Re-evaluating dorsolateral prefrontal cortex activation during working memory in schizophrenia.
        Schizophr Res. 2009; 108: 143-150
        • Wager T.D.
        • Keller M.C.
        • Lacey S.C.
        • Jonides J.
        Increased sensitivity in neuroimaging analyses using robust regression.
        Neuroimage. 2005; 26: 99-113
        • Anticevic A.
        • Cole M.W.
        • Murray J.D.
        • Corlett P.R.
        • Wang X.J.
        • Krystal J.H.
        The role of default network deactivation in cognition and disease.
        Trends Cogn Sci. 2012; 16: 584-592
        • Kim D.I.
        • Manoach D.S.
        • Mathalon D.H.
        • Turner J.A.
        • Mannell M.
        • Brown G.G.
        • et al.
        Dysregulation of working memory and default-mode networks in schizophrenia using independent component analysis, an fBIRN and MCIC study.
        Hum Brain Mapp. 2009; 30: 3795-3811
        • Metzak P.D.
        • Riley J.D.
        • Wang L.
        • Whitman J.C.
        • Ngan E.T.C.
        • Woodward T.S.
        Decreased efficiency of task-positive and task-negative networks during working memory in schizophrenia.
        Schizophr Bull. 2012; 38: 803-813
        • Pomarol-Clotet E.
        • Salvador R.
        • Sarro S.
        • Gomar J.
        • Vila F.
        • Martinez A.
        • et al.
        Failure to deactivate in the prefrontal cortex in schizophrenia: Dysfunction of the default mode network?.
        Psychol Med. 2008; 38: 1185-1193
        • Anticevic A.
        • Repovs G.
        • Shulman G.L.
        • Barch D.M.
        When less is more: TPJ and default network deactivation during encoding predicts working memory performance.
        Neuroimage. 2010; 49: 2638-2648
        • Gusnard D.A.
        • Akbudak E.
        • Shulman G.L.
        • Raichle M.E.
        Medial prefrontal cortex and self-referential mental activity: Relation to a default mode of brain function.
        Proc Natl Acad Sci U S A. 2001; 98: 4259-4264
        • Macrae C.N.
        • Moran J.M.
        • Heatherton T.F.
        • Banfield J.F.
        • Kelley W.M.
        Medial prefrontal activity predicts memory for self.
        Cereb Cortex. 2004; 14: 647-654
        • Mitchell J.P.
        • Banaji M.R.
        • Macrae C.N.
        The link between social cognition and self-referential thought in the medial prefrontal cortex.
        J Cogn Neurosci. 2005; 17: 1306-1315
        • Addis D.R.
        • Wong A.T.
        • Schacter D.L.
        Remembering the past and imagining the future: Common and distinct neural substrates during event construction and elaboration.
        Neuropsychologia. 2007; 45: 1363-1377
        • Maddock R.J.
        • Garrett A.S.
        • Buonocore M.H.
        Remembering familiar people: The posterior cingulate cortex and autobiographical memory retrieval.
        Neuroscience. 2001; 104: 667-676
        • Steinvorth S.
        • Corkin S.
        • Halgren E.
        Ecphory of autobiographical memories: An fMRI study on recent and remote memory retrieval.
        Neuroimage. 2006; 30: 285-298
        • Wagner A.D.
        • Shannon B.J.
        • Kahn I.
        • Buckner R.L.
        Parietal lobe contributions to episodic memory retrieval.
        Trends Cogn Sci. 2005; 9: 445-453
        • Woods S.W.
        Chlorpromazine equivalent doses for the newer atypical antipsychotics.
        J Clin Psychiatry. 2003; 64: 663-667

      Linked Article

      • Revisiting the Inverted-U Hypothesis of Working Memory Activation in Schizophrenia
        Biological PsychiatryVol. 80Issue 8
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          Cognitive impairment is a debilitating and treatment-resistant aspect of schizophrenia that is associated with poorer functional outcome. Particularly, deficits in working memory (WM), a key component of higher order cognition, have been studied using functional neuroimaging for decades (1). These studies failed to produce converging findings, likely reflecting disease heterogeneity and methodologic differences. The article by Van Snellenberg et al. (2) in this issue of Biological Psychiatry reveals brain activation associated with WM deficits in schizophrenia using a clever task design and sophisticated imaging and statistical methods.
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