Cortical inhibition, excitation, and connectivity in schizophrenia: a review of insights from transcranial magnetic stimulation.

Schizophrenia (SCZ) is a debilitating mental illness with an elusive pathophysiology. Over the last decade, theories emphasizing cortical dysfunction have received increasing attention to explain the heterogeneous symptoms experienced in SCZ. Transcranial magnetic stimulation (TMS) is a noninvasive form of brain stimulation that is particularly suited to probing the fidelity of specific excitatory and inhibitory neuronal populations in conscious humans. In this study, we review the contribution of TMS in assessing inhibitory and excitatory neuronal populations and their long-range connections in SCZ. In addition, we discuss insights from combined TMS and electroencephalography into the functional consequences of impaired excitation/inhibition on cortical oscillations in SCZ.

[1]  P. Fitzgerald,et al.  Suppression of γ-Oscillations in the Dorsolateral Prefrontal Cortex following Long Interval Cortical Inhibition: A TMS–EEG Study , 2009, Neuropsychopharmacology.

[2]  Alexander Münchau,et al.  Magnetic stimulation of human premotor or motor cortex produces interhemispheric facilitation through distinct pathways , 2006, The Journal of physiology.

[3]  S. Kapur,et al.  Evidence for impaired cortical inhibition in schizophrenia using transcranial magnetic stimulation. , 2002, Archives of general psychiatry.

[4]  Jessica A. Cardin,et al.  Driving fast-spiking cells induces gamma rhythm and controls sensory responses , 2009, Nature.

[5]  G. Tononi,et al.  Reduced evoked gamma oscillations in the frontal cortex in schizophrenia patients: a TMS/EEG study. , 2008, American Journal of Psychiatry.

[6]  R. Gur,et al.  GABAB-mediated rescue of altered excitatory–inhibitory balance, gamma synchrony and behavioral deficits following constitutive NMDAR-hypofunction , 2012, Translational Psychiatry.

[7]  J. Gold.  Cognitive deficits as treatment targets in schizophrenia , 2004, Schizophrenia Research.

[8]  A. Sampson,et al.  Gene Expression Deficits in a Subclass of GABA Neurons in the Prefrontal Cortex of Subjects with Schizophrenia , 2003, The Journal of Neuroscience.

[9]  K. Deisseroth,et al.  Parvalbumin neurons and gamma rhythms enhance cortical circuit performance , 2009, Nature.

[10]  Alvaro Pascual-Leone,et al.  Motor cortical excitability in schizophrenia , 2002, Biological Psychiatry.

[11]  P. Fitzgerald,et al.  Evaluating the Relationship between Long Interval Cortical Inhibition, Working Memory and Gamma Band Activity in the Dorsolateral Prefrontal Cortex , 2008, Clinical EEG and neuroscience.

[12]  S. Potkin,et al.  Selective alterations in gene expression for NMDA receptor subunits in prefrontal cortex of schizophrenics , 1996, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[13]  Paul B. Fitzgerald,et al.  Reduced motor facilitation during action observation in schizophrenia: A mirror neuron deficit? , 2008, Schizophrenia Research.

[14]  E. G. Jones,et al.  Gene expression for glutamic acid decarboxylase is reduced without loss of neurons in prefrontal cortex of schizophrenics. , 1995, Archives of general psychiatry.

[15]  M. Hallett,et al.  Human motor evoked responses to paired transcranial magnetic stimuli. , 1992, Electroencephalography and clinical neurophysiology.

[16]  M. Hallett,et al.  Spinal motor neuron excitability during the silent period after cortical stimulation. , 1991, Electroencephalography and clinical neurophysiology.

[17]  P. Fitzgerald,et al.  A transcranial magnetic stimulation study of the effects of olanzapine and risperidone on motor cortical excitability in patients with schizophrenia , 2002, Psychopharmacology.

[18]  R. Deisz,et al.  GABAB receptor-mediated effects in human and rat neocortical neurones in vitro , 1999, Neuropharmacology.

[19]  P. Fitzgerald,et al.  Long-Interval Cortical Inhibition from the Dorsolateral Prefrontal Cortex: a TMS–EEG Study , 2008, Neuropsychopharmacology.

[20]  P. Schwenkreis,et al.  Influence of the N-methyl-d-aspartate antagonist memantine on human motor cortex excitability , 1999, Neuroscience Letters.

[21]  Ullrich K. H. Ecker,et al.  Increased cortical inhibition deficits in first-episode schizophrenia with comorbid cannabis abuse , 2009, Psychopharmacology.

[22]  Lief E. Fenno,et al.  Neocortical excitation/inhibition balance in information processing and social dysfunction , 2011, Nature.

[23]  B Boroojerdi,et al.  Transcallosal inhibition and motor conduction studies in patients with schizophrenia using transcranial magnetic stimulation. , 1999, The British journal of psychiatry : the journal of mental science.

[24]  R. Hanajima,et al.  Magnetic stimulation over the cerebellum in humans , 1995, Annals of neurology.

[25]  Giacomo Koch,et al.  Focal Stimulation of the Posterior Parietal Cortex Increases the Excitability of the Ipsilateral Motor Cortex , 2007, The Journal of Neuroscience.

[26]  Babak Boroojerdi,et al.  Transcallosal inhibition in cortical and subcortical cerebral vascular lesions , 1996, Journal of the Neurological Sciences.

[27]  P. Fitzgerald,et al.  Gamma oscillations in schizophrenia: Mechanisms and clinical significance , 2011, Brain Research.

[28]  B. Day,et al.  Interhemispheric inhibition of the human motor cortex. , 1992, The Journal of physiology.

[29]  P. Fitzgerald,et al.  A transcranial magnetic stimulation study of abnormal cortical inhibition in schizophrenia , 2003, Psychiatry Research.

[30]  Jessica A. Cardin,et al.  A critical role for NMDA receptors in parvalbumin interneurons for gamma rhythm induction and behavior , 2011, Molecular Psychiatry.

[31]  P. Fitzgerald,et al.  A transcranial magnetic stimulation study of inhibitory deficits in the motor cortex in patients with schizophrenia , 2002, Psychiatry Research: Neuroimaging.

[32]  Robert Chen,et al.  Exploring the connectivity between the cerebellum and motor cortex in humans , 2004, The Journal of physiology.

[33]  Christian Grefkes,et al.  Deficient Inhibitory Cortical Networks in Antipsychotic-Naive Subjects at Risk of Developing First-Episode Psychosis and First-Episode Schizophrenia Patients: A Cross-Sectional Study , 2012, Biological Psychiatry.

[34]  D. Lewis,et al.  Cortical inhibitory neurons and schizophrenia , 2005, Nature Reviews Neuroscience.

[35]  Edward T. Bullmore,et al.  Schizophrenia, neuroimaging and connectomics , 2012, NeuroImage.

[36]  P. Fitzgerald,et al.  Reduced plastic brain responses in schizophrenia: a transcranial magnetic stimulation study , 2004, Schizophrenia Research.

[37]  Robert Chen,et al.  Increased cortical inhibition in persons with schizophrenia treated with clozapine , 2008, Journal of psychopharmacology.

[38]  Á. Pascual-Leone,et al.  Transcranial Magnetic Stimulation: A Neuroscientific Probe of Cortical Function in Schizophrenia , 2011, Biological Psychiatry.

[39]  Karl J. Friston,et al.  Dysconnection in Schizophrenia: From Abnormal Synaptic Plasticity to Failures of Self-monitoring , 2009, Schizophrenia bulletin.

[40]  B. Christensen,et al.  Reduced cerebellar inhibition in schizophrenia: a preliminary study. , 2005, The American journal of psychiatry.

[41]  Paul B. Fitzgerald,et al.  GABA and cortical inhibition in motor and non-motor regions using combined TMS–EEG: A time analysis , 2009, Clinical Neurophysiology.

[42]  Nigel C Rogasch,et al.  Assessing cortical network properties using TMS–EEG , 2013, Human brain mapping.

[43]  Á. Pascual-Leone,et al.  Motor facilitation while observing hand actions: specificity of the effect and role of observer's orientation. , 2002, Journal of neurophysiology.

[44]  G. Rizzolatti,et al.  Motor facilitation during action observation: a magnetic stimulation study. , 1995, Journal of neurophysiology.

[45]  D. McCormick,et al.  GABA as an inhibitory neurotransmitter in human cerebral cortex. , 1989, Journal of neurophysiology.

[46]  Patrick Ragert,et al.  Contribution of transcranial magnetic stimulation to the understanding of cortical mechanisms involved in motor control , 2008, The Journal of physiology.

[47]  Ullrich K. H. Ecker,et al.  Reduced cortical inhibition in first-episode schizophrenia , 2008, Schizophrenia Research.

[48]  R. Ilmoniemi,et al.  Neuronal responses to magnetic stimulation reveal cortical reactivity and connectivity , 1997, Neuroreport.

[49]  M. Nitsche,et al.  Dysfunctional long-term potentiation-like plasticity in schizophrenia revealed by transcranial direct current stimulation , 2011, Behavioural Brain Research.

[50]  G. Tononi,et al.  Breakdown of Cortical Effective Connectivity During Sleep , 2005, Science.

[51]  Walter Paulus,et al.  Demonstration of facilitatory I wave interaction in the human motor cortex by paired transcranial magnetic stimulation , 1998, The Journal of physiology.

[52]  Karl J. Friston,et al.  Schizophrenia: a disconnection syndrome? , 1995, Clinical neuroscience.

[53]  Robert Chen,et al.  Interactions between two different inhibitory systems in the human motor cortex , 2001, The Journal of physiology.

[54]  Robert Chen,et al.  Evidence for gamma inhibition deficits in the dorsolateral prefrontal cortex of patients with schizophrenia. , 2010, Brain : a journal of neurology.

[55]  W. Singer,et al.  Abnormal neural oscillations and synchrony in schizophrenia , 2010, Nature Reviews Neuroscience.

[56]  T. Schneider-Axmann,et al.  Motor Circuit Abnormalities in First-episode Schizophrenia Assessed with Transcranial Magnetic Stimulation , 2009, Pharmacopsychiatry.

[57]  D. Lewis,et al.  Decreased dendritic spine density on prefrontal cortical pyramidal neurons in schizophrenia. , 2000, Archives of general psychiatry.

[58]  B. Christensen,et al.  The mechanisms of interhemispheric inhibition in the human motor cortex , 2002, The Journal of physiology.

[59]  J. Rothwell,et al.  Decreased corticospinal excitability after subthreshold 1 Hz rTMS over lateral premotor cortex , 2001, Neurology.

[60]  J. Coyle,et al.  Glutamate and Schizophrenia: Beyond the Dopamine Hypothesis , 2006, Cellular and Molecular Neurobiology.

[61]  D. Centonze,et al.  Genetic variants of the NMDA receptor influence cortical excitability and plasticity in humans. , 2011, Journal of neurophysiology.

[62]  M. Nitsche,et al.  Physiological Basis of Transcranial Direct Current Stimulation , 2011, The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry.

[63]  P. Fries.  A mechanism for cognitive dynamics: neuronal communication through neuronal coherence , 2005, Trends in Cognitive Sciences.

[64]  M Hallett,et al.  Dextromethorphan decreases the excitability of the human motor cortex , 1998, Neurology.

[65]  J. Rothwell,et al.  Direct demonstration of the effect of lorazepam on the excitability of the human motor cortex , 2000, Clinical Neurophysiology.

[66]  O. Sporns,et al.  Complex brain networks: graph theoretical analysis of structural and functional systems , 2009, Nature Reviews Neuroscience.

[67]  David A Lewis,et al.  Conserved regional patterns of GABA-related transcript expression in the neocortex of subjects with schizophrenia. , 2008, The American journal of psychiatry.

[68]  E. Bullmore,et al.  Meta-analysis of diffusion tensor imaging studies in schizophrenia , 2009, Schizophrenia Research.

[69]  E. Kunesch,et al.  Dysfunction of transcallosally mediated motor inhibition and callosal morphology in patients with schizophrenia , 2001, Acta psychiatrica Scandinavica.

[70]  N. Davey,et al.  Effects of antipsychotic medication on electromyographic responses to transcranial magnetic stimulation of the motor cortex in schizophrenia , 1997, Journal of neurology, neurosurgery, and psychiatry.

[71]  Bill Bynum,et al.  Lancet , 2015, The Lancet.

[72]  J. Lisman.  Excitation, inhibition, local oscillations, or large-scale loops: what causes the symptoms of schizophrenia? , 2012, Current Opinion in Neurobiology.

[73]  Paul B. Fitzgerald,et al.  Repetitive transcranial magnetic stimulation reveals abnormal plastic response to premotor cortex stimulation in schizophrenia , 2004, Biological Psychiatry.

[74]  Giacomo Koch,et al.  Impaired inter-hemispheric facilitatory connectivity in schizophrenia , 2011, Clinical Neurophysiology.

[75]  Robert Chen,et al.  The effects of inhibitory and facilitatory intracortical circuits on interhemispheric inhibition in the human motor cortex , 2007, The Journal of physiology.

[76]  V. Litvak,et al.  Differences in TMS-evoked responses between schizophrenia patients and healthy controls can be observed without a dedicated EEG system , 2010, Clinical Neurophysiology.

[77]  O. Snead,et al.  Evidence that clozapine directly interacts on the GABAB receptor , 2011, Neuroreport.

[78]  P. Fitzgerald,et al.  A transcranial magnetic stimulation study of transcallosal inhibition and facilitation in schizophrenia , 2008, Journal of Clinical Neuroscience.

[79]  Robert Chen,et al.  Reliability of long-interval cortical inhibition in healthy human subjects: a TMS-EEG study. , 2010, Journal of neurophysiology.

[80]  G. Rizzolatti,et al.  The mirror-neuron system. , 2004, Annual review of neuroscience.

[81]  M. Hallett.  Transcranial Magnetic Stimulation: A Primer , 2007, Neuron.

[82]  Zafiris J Daskalakis,et al.  Mechanisms underlying long-interval cortical inhibition in the human motor cortex: a TMS-EEG study. , 2013, Journal of neurophysiology.

[83]  P. Rossini,et al.  Consensus paper: Combining transcranial stimulation with neuroimaging , 2009, Brain Stimulation.

[84]  J. McGrath,et al.  A Systematic Review of the Prevalence of Schizophrenia , 2005, PLoS medicine.

[85]  Jerome J Maller,et al.  Cortical Inhibition in Motor and Non-Motor Regions: A Combined TMS-EEG Study , 2008, Clinical EEG and neuroscience.

[86]  P. Pasqualetti,et al.  Ketamine Increases Human Motor Cortex Excitability to Transcranial Magnetic Stimulation , 2003, The Journal of physiology.

[87]  B. Langguth,et al.  Cortical excitability in neuroleptic-naive first-episode schizophrenic patients , 2004, Schizophrenia Research.

[88]  Lakshminarayan V. Chinta,et al.  Disrupted cortical conductivity in schizophrenia: TMS-EEG study. , 2014, Cerebral cortex.

[89]  L. Niehaus,et al.  Abnormalities of inhibitory neuronal mechanisms in the motor cortex of patients with schizophrenia. , 2004, Pharmacopsychiatry.

[90]  鯨井 隆.  Corticocortical inhibition in human motor cortex , 1994 .

[91]  G. Rizzolatti,et al.  The mirror neuron system. , 2009, Archives of neurology.

[92]  B. Mulsant,et al.  The Role of the Corpus Callosum in Transcranial Magnetic Stimulation Induced Interhemispheric Signal Propagation , 2010, Biological Psychiatry.

[93]  M. Massimini,et al.  Natural Frequencies of Human Corticothalamic Circuits , 2009, The Journal of Neuroscience.

[94]  M. Nitsche,et al.  Abnormal bihemispheric responses in schizophrenia patients following cathodal transcranial direct stimulation , 2012, European Archives of Psychiatry and Clinical Neuroscience.

[95]  J. Rothwell,et al.  Interhemispheric interaction between human dorsal premotor and contralateral primary motor cortex , 2004, The Journal of physiology.

[96]  P. Fitzgerald,et al.  Neurological soft signs in schizophrenia: Investigating motor overflow , 2009, The world journal of biological psychiatry : the official journal of the World Federation of Societies of Biological Psychiatry.

[97]  P. Uhlhaas.  Dysconnectivity, large-scale networks and neuronal dynamics in schizophrenia , 2013, Current Opinion in Neurobiology.

[98]  Walter Paulus,et al.  The effect of lorazepam on the motor cortical excitability in man , 1996, Experimental Brain Research.

[99]  P. Fitzgerald,et al.  Evidence for impaired long-term potentiation in schizophrenia and its relationship to motor skill learning. , 2008, Cerebral cortex.

[100]  Giulio Tononi,et al.  Probing thalamic integrity in schizophrenia using concurrent transcranial magnetic stimulation and functional magnetic resonance imaging. , 2012, Archives of general psychiatry.

[101]  W. Paulus,et al.  Pharmacological control of facilitatory I-wave interaction in the human motor cortex. A paired transcranial magnetic stimulation study. , 1998, Electroencephalography and clinical neurophysiology.

[102]  G. Tononi,et al.  Reduced natural oscillatory frequency of frontal thalamocortical circuits in schizophrenia. , 2012, Archives of general psychiatry.

[103]  P. Fitzgerald,et al.  A study of transcallosal inhibition in schizophrenia using transcranial magnetic stimulation , 2002, Schizophrenia Research.

[104]  T. Kaneko,et al.  Glutamatergic deficits and parvalbumin-containing inhibitory neurons in the prefrontal cortex in schizophrenia , 2009, BMC psychiatry.

[105]  O. Paulsen,et al.  The roles of GABAB receptors in cortical network activity. , 2010, Advances in pharmacology.

[106]  Vladimir Litvak,et al.  Artifact correction and source analysis of early electroencephalographic responses evoked by transcranial magnetic stimulation over primary motor cortex , 2007, NeuroImage.

[107]  P. Fitzgerald,et al.  Using transcranial magnetic stimulation to investigate the cortical origins of motor overflow: a study in schizophrenia and healthy controls , 2007, Psychological Medicine.

[108]  M. Nitsche,et al.  Impaired long-term depression in schizophrenia: A cathodal tDCS pilot study , 2012, Brain Stimulation.

[109]  Giacomo Koch,et al.  Connectivity Between Posterior Parietal Cortex and Ipsilateral Motor Cortex Is Altered in Schizophrenia , 2008, Biological Psychiatry.

[110]  P. Gourzis,et al.  Cortical motor neurophysiology of patients with schizophrenia: A study using transcranial magnetic stimulation , 2010, Psychiatry Research.

[111]  P. Fitzgerald,et al.  The Relationship Between Cortical Inhibition, Antipsychotic Treatment, and the Symptoms of Schizophrenia , 2009, Biological Psychiatry.

[112]  J. Meador-Woodruff,et al.  Lamina-Specific Abnormalities of NMDA Receptor-Associated Postsynaptic Protein Transcripts in the Prefrontal Cortex in Schizophrenia and Bipolar Disorder , 2008, Neuropsychopharmacology.

[113]  M. C. Saka,et al.  Cortical inhibition in first-degree relatives of schizophrenic patients assessed with transcranial magnetic stimulation. , 2005, The international journal of neuropsychopharmacology.

[114]  P H Ellaway,et al.  An Investigation of Motor Function in Schizophrenia using Transcranial Magnetic Stimulation of the Motor Cortex , 1996, British Journal of Psychiatry.