Can Repetitive Magnetic Stimulation Improve Cognition in Schizophrenia? Pilot Data from a Randomized Controlled Trial


      Working memory represents a core cognitive domain that is impaired in schizophrenia for which there are currently no satisfactory treatments. Repetitive transcranial magnetic stimulation (rTMS) targeted over the dorsolateral prefrontal cortex has been shown to modulate neurophysiological mechanisms linked to working memory in schizophrenia and improves working memory performance in healthy subjects and might therefore represent a treatment modality for schizophrenia patients. The objectives were to evaluate the effects of rTMS on working memory performance in schizophrenia patients and evaluate whether rTMS normalizes performance to healthy subject levels.


      In a 4-week randomized double-blind sham-controlled pilot study design, 27 medicated schizophrenia patients were tested at the Centre for Addiction and Mental Health (a university teaching hospital that provides psychiatric care to a large urban catchment area and serves as a tertiary referral center for the province of Ontario). Patients performed the verbal working memory n-back task before and after rTMS magnetic resonance image targeted bilaterally sequentially to left and right dorsolateral prefrontal cortex 750 pulses/side at 20 Hz for 20 treatments. The main outcome measure was mean magnitude of change in the n-back accuracy for target responses with active (n=13) or sham (n=12) rTMS treatment course.


      The rTMS significantly improved 3-back accuracy for targets compared with placebo sham (Cohen’s d=.92). The improvement in 3-back accuracy was also found to be at a level comparable to healthy subjects.


      These pilot data suggest that bilateral rTMS might be a novel, efficacious, and safe treatment for working memory deficits in patients with schizophrenia.

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        • Carpenter W.T.
        • Buchanan R.W.
        N Engl J Med. 1994; 330: 681-690
        • Knapp M.
        Costs of schizophrenia.
        Br J Psychiatry. 1997; 171: 509-518
        • Green M.F.
        What are the functional consequences of neurocognitive deficits in schizophrenia?.
        Am J Psychiatry. 1996; 153: 321-330
        • Green M.F.
        Cognitive impairment and functional outcome in schizophrenia and bipolar disorder.
        J Clin Psychiatry. 2006; 67: e12
        • Green M.F.
        • Kern R.S.
        • Heaton R.K.
        Longitudinal studies of cognition and functional outcome in schizophrenia: Implications for MATRICS..
        Schizophr Res. 2004; 72: 41-51
        • Forbes N.F.
        • Carrick L.A.
        • McIntosh A.M.
        • Lawrie S.M.
        Working memory in schizophrenia: A meta-analysis.
        Psychol Med. 2009; 39: 889-905
        • Baddeley A.
        Working Memory.
        Clarendon Press, Oxford1986
        • Baddeley A.
        Working memory.
        Science. 1992; 255: 556-559
        • Baddeley A.
        The episodic buffer: A new component of working memory?.
        Trends Cogn Sci. 2000; 4: 417-423
        • Petrides M.
        The role of the mid-dorsolateral prefrontal cortex in working memory.
        Exp Brain Res. 2000; 133: 44-54
        • Owen A.M.
        • McMillan K.M.
        • Laird A.R.
        • Bullmore E.
        N-back working memory paradigm: A meta-analysis of normative functional neuroimaging studies.
        Hum Brain Mapp. 2005; 25: 46-59
        • Barch D.M.
        The cognitive neuroscience of schizophrenia.
        Annu Rev Clin Psychol. 2005; 1: 321-353
        • D’Esposito M.
        • Aguirre G.K.
        • Zarahn E.
        • Ballard D.
        • Shin R.K.
        • Lease J.
        Functional MRI studies of spatial and nonspatial working memory.
        Brain Res Cogn Brain Res. 1998; 7: 1-13
        • 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
        • Barch D.M.
        • Carter C.S.
        • Braver T.S.
        • Sabb F.W.
        • MacDonald 3rd, A.
        • Noll D.C.
        • et al.
        Selective deficits in prefrontal cortex function in medication-naive patients with schizophrenia.
        Arch Gen Psychiatry. 2001; 58: 280-288
        • Barch D.M.
        • Csernansky J.G.
        • Conturo T.
        • Snyder A.Z.
        Working and long-term memory deficits in schizophrenia: Is there a common prefrontal mechanism?.
        J Abnorm Psychol. 2002; 111: 478-494
        • 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: Methodological issues illustrated in a study of working memory in schizophrenia.
        Neuropsychopharmacology. 1998; 18: 186-196
        • 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
        • 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
        • 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
        • Cho R.Y.
        • Konecky R.O.
        • Carter C.S.
        Impairments in frontal cortical gamma synchrony and cognitive control in schizophrenia.
        Proc Natl Acad Sci U S A. 2006; 103: 19878-19883
        • Barr M.S.
        • Farzan F.
        • Tran L.C.
        • Chen R.
        • Fitzgerald P.B.
        • Daskalakis Z.J.
        Evidence for excessive frontal evoked gamma oscillatory activity in schizophrenia during working memory.
        Schizophr Res. 2010; 121: 146-152
        • Barr M.S.
        • Farzan F.
        • Arenovich T.
        • Chen R.
        • Fitzgerald P.B.
        • Daskalakis Z.J.
        The effect of repetitive transcranial magnetic stimulation on gamma oscillatory activity in schizophrenia.
        PLoS One. 2011; 6: e22627
        • Basar-Eroglu C.
        • Brand A.
        • Hildebrandt H.
        • Karolina Kedzior K.
        • Mathes B.
        • Schmiedt C.
        Working memory related gamma oscillations in schizophrenia patients.
        Int J Psychophysiol. 2007; 64: 39-45
        • Haenschel C.
        • Bittner R.A.
        • Waltz J.
        • Haertling F.
        • Wibral M.
        • Singer W.
        • et al.
        Cortical oscillatory activity is critical for working memory as revealed by deficits in early-onset schizophrenia.
        J Neurosci. 2009; 29: 9481-9489
        • 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
        • Barr M.S.
        • Farzan F.
        • Rusjan P.M.
        • Chen R.
        • Fitzgerald P.B.
        • Daskalakis Z.J.
        Potentiation of gamma oscillatory activity through repetitive transcranial magnetic stimulation of the dorsolateral prefrontal cortex.
        Neuropsychopharmacology. 2009; 34: 2359-2367
        • 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
        • Lewis D.A.
        • Hashimoto T.
        • Volk D.W.
        Cortical inhibitory neurons and schizophrenia.
        Nat Rev Neurosci. 2005; 6: 312-324
        • Farzan F.
        • Barr M.S.
        • Levinson A.J.
        • Chen R.
        • Wong W.
        • Fitzgerald P.B.
        • et al.
        Evidence for gamma inhibition deficits in the dorsolateral prefrontal cortex of patients with schizophrenia.
        Brain. 2010; 133: 1505-1514
        • Spencer K.M.
        • Niznikiewicz M.A.
        • Shenton M.E.
        • McCarley R.W.
        Sensory-evoked gamma oscillations in chronic schizophrenia.
        Biol Psychiatry. 2008; 63: 744-747
        • Light G.A.
        • Hsu J.L.
        • Hsieh M.H.
        • Meyer-Gomes K.
        • Sprock J.
        • Swerdlow N.R.
        • et al.
        Gamma band oscillations reveal neural network cortical coherence dysfunction in schizophrenia patients.
        Biol Psychiatry. 2006; 60: 1231-1240
        • Oh S.Y.
        • Kim Y.K.
        Adjunctive treatment of bimodal repetitive transcranial magnetic stimulation (rTMS) in pharmacologically non-responsive patients with schizophrenia: A preliminary study.
        Prog Neuropsychopharmacol Biol Psychiatry. 2011; 35: 1938-1943
        • Preston G.
        • Anderson E.
        • Silva C.
        • Goldberg T.
        • Wassermann E.M.
        Effects of 10 Hz rTMS on the neural efficiency of working memory.
        J Cogn Neurosci. 2009; 22: 447-456
        • Hamidi M.
        • Tononi G.
        • Postle B.R.
        Evaluating the role of prefrontal and parietal cortices in memory-guided response with repetitive transcranial magnetic stimulation.
        Neuropsychologia. 2009; 47: 295-302
        • Oldfield R.C.
        The assessment and analysis of handedness: The Edinburgh inventory.
        Neuropsychologia. 1971; 9: 97-113
        • Spitzer R.L.
        Diagnostic and Statistical Manual of Mental Disorders.
        4th Edition. American Psychiatric Association, Washington, DC1994
        • Kay S.R.
        • Fiszbein A.
        • Opler L.A.
        The Positive and Negative Syndrome Scale (PANSS) for schizophrenia.
        Schizophr Bull. 1987; 13: 261-276
        • Andreasen N.C.
        The Scale for the Assessment of Negative Symptoms (SANS): conceptual and theoretical foundations.
        Br J Psychiatry Suppl. 1989; : 49-58
        • Addington D.
        • Addington J.
        • Maticka-Tyndale E.
        Assessing depression in schizophrenia: The Calgary Depression Scale.
        Br J Psychiatry Suppl. 1993; : 39-44
        • Chen R.
        • Gerloff C.
        • Classen J.
        • Wassermann E.M.
        • Hallett M.
        • Cohen L.G.
        Safety of different inter-train intervals for repetitive transcranial magnetic stimulation and recommendations for safe ranges of stimulation parameters.
        Electroencephalogr Clin Neurophysiol. 1997; 105: 415-421
        • Fitzgerald P.B.
        • Oxley T.J.
        • Laird A.R.
        • Kulkarni J.
        • Egan G.F.
        • Daskalakis Z.J.
        An analysis of functional neuroimaging studies of dorsolateral prefrontal cortical activity in depression.
        Psychiatry Res. 2006; 148: 33-45
        • Woods SW
        Chlorpromazine equivalent doses for the newer atypical antipsychotics.
        J Clin Psychiatry. 2003; 64: 663-667
        • Barr MS
        • Farzan F.
        • Tran L.C.
        • Fitzgerald P.B.
        • Daskalakis Z.J.
        A randomized controlled trial of sequentially bilateral prefrontal cortex repetitive transcranial magnetic stimulation in the treatment of negative symptoms in schizophrenia.
        Brain Stimul. 2012; 5: 337-346
        • McGurk S.R.
        • Twamley E.W.
        • Sitzer D.I.
        • McHugo G.J.
        • Mueser KT
        A meta-analysis of cognitive remediation in schizophrenia.
        Am J Psychiatry. 2007; 164: 1791-1802
        • Wykes T.
        • Huddy V.
        • Cellard C.
        • McGurk S.R.
        • Czobor P.
        A meta-analysis of cognitive remediation for schizophrenia: Methodology and effect sizes.
        Am J Psychiatry. 2011; 168: 472-485
        • Barch DM
        • Carter C.S.
        Amphetamine improves cognitive function in medicated individuals with schizophrenia and in healthy volunteers.
        Schizophr Res. 2005; 77: 43-58
        • Menzies L.
        • Ooi C.
        • Kamath S.
        • Suckling J.
        • McKenna P.
        • Fletcher P.
        • et al.
        Effects of gamma-aminobutyric acid-modulating drugs on working memory and brain function in patients with schizophrenia.
        Arch Gen Psychiatry. 2007; 64: 156-167
        • Whittington MA
        • Traub R.D.
        • Jefferys J.G.
        Synchronized oscillations in interneuron networks driven by metabotropic glutamate receptor activation.
        Nature. 1995; 373: 612-615
        • Daskalakis Z.J.
        • Christensen B.K.
        • Fitzgerald P.B.
        • Chen R.
        Dysfunctional neural plasticity in patients with schizophrenia.
        Arch Gen Psychiatry. 2008; 65: 378-385
        • Frantseva MV
        • Fitzgerald P.B.
        • Chen R.
        • Moller B.
        • Daigle M.
        • Daskalakis Z.J.
        Evidence for impaired long-term potentiation in schizophrenia and its relationship to motor skill learning.
        Cereb Cortex. 2008; 18: 990-996
        • Thomas R.P.
        • Dougherty M.R.
        • Sprenger A.M.
        • Harbison J.I.
        Diagnostic hypothesis generation and human judgment.
        Psychol Rev. 2008; 115: 155-185
      1. Harbison JI, Atkins SM, Dougherty MR (2011): N-back Training Task Performance: Analysis and Model. Paper presented at: The Annual Meeting of the Cognitive Science Society; July 20–23, 2011; Boston, Massachusetts.

        • Sachdev P.
        • Loo C.
        • Mitchell P.
        • Malhi G.
        Transcranial magnetic stimulation for the deficit syndrome of schizophrenia: A pilot investigation.
        Psychiatry Clin Neurosci. 2005; 59: 354-357
        • Fitzgerald P.B.
        • Herring S.
        • Hoy K.
        • McQueen S.
        • Segrave R.
        • Kulkarni J.
        • et al.
        A study of the effectiveness of bilateral transcranial magnetic stimulation in the treatment of the negative symptoms of schizophrenia.
        Brain Stimul. 2008; 1: 27-32
        • Norman GR
        • Streiner D.L.
        Biostatistics: The Bare Essentials.
        2nd ed. B.C. Decker, Hamilton, Ontario, Canada2000
        • Sanacora G.
        • Mason G.F.
        • Krystal J.H.
        Impairment of GABAergic transmission in depression: New insights from neuroimaging studies.
        Crit Rev Neurobiol. 2000; 14: 23-45
        • Daskalakis Z.J.
        • Farzan F.
        • Barr M.S.
        • Maller J.J.
        • Chen R.
        • Fitzgerald P.B.
        Long-interval cortical inhibition from the dorsolateral prefrontal cortex: A TMS-EEG study.
        Neuropsychopharmacology. 2008; 33: 2860-2869