Physiological Basis of Transcranial Direct Current Stimulation

Since the rediscovery of transcranial direct current stimulation (tDCS) about 10 years ago, interest in tDCS has grown exponentially. A noninvasive stimulation technique that induces robust excitability changes within the stimulated cortex, tDCS is increasingly being used in proof-of-principle and stage IIa clinical trials in a wide range of neurological and psychiatric disorders. Alongside these clinical studies, detailed work has been performed to elucidate the mechanisms underlying the observed effects. In this review, the authors bring together the results from these pharmacological, neurophysiological, and imaging studies to describe their current knowledge of the physiological effects of tDCS. In addition, the theoretical framework for how tDCS affects motor learning is proposed.

[1]  P. Kellaway,et al.  The part played by electric fish in the early history of bioelectricity and electrotherapy. , 1946, Bulletin of the history of medicine.

[2]  O. Creutzfeldt,et al.  Influence of transcortical d-c currents on cortical neuronal activity. , 1962, Experimental neurology.

[3]  L. Bindman,et al.  The action of brief polarizing currents on the cerebral cortex of the rat (1) during current flow and (2) in the production of long‐lasting after‐effects , 1964, The Journal of physiology.

[4]  D. Purpura,et al.  INTRACELLULAR ACTIVITIES AND EVOKED POTENTIAL CHANGES DURING POLARIZATION OF MOTOR CORTEX. , 1965, Journal of neurophysiology.

[5]  I. Gartside,et al.  Mechanisms of Sustained Increases of Firing Rate of Neurones in the Rat Cerebral Cortex after Polarization: Role of Protein Synthesis , 1968, Nature.

[6]  D. A. Driscoll,et al.  Current Distribution in the Brain From Surface Electrodes , 1968, Anesthesia and analgesia.

[7]  I. Gartside,et al.  Mechanisms of Sustained Increases of Firing Rate of Neurones in the Rat Cerebral Cortex after Polarization: Reverberating Circuits or Modification of Synaptic Conductance? , 1968, Nature.

[8]  G. PFURTSCHELLER,et al.  Spektralanalyse des EEG: vor, während und nach einer extracranialen Stimulation am Menschen , 1970 .

[9]  [Spectrum analysis of EEG: before, during and after extracranial stimulation in man]. , 1970, Elektro Medizin; Biomedizin und Technik.

[10]  T. Bliss,et al.  Long‐lasting potentiation of synaptic transmission in the dentate area of the anaesthetized rabbit following stimulation of the perforant path , 1973, The Journal of physiology.

[11]  Serafetinides Ea,et al.  Intracerebral current levels in man during electrosleep therapy. , 1975 .

[12]  T. Sejnowski Statistical constraints on synaptic plasticity. , 1977, Journal of theoretical biology.

[13]  H. Akil,et al.  Behavioral neurochemistry: neuroregulators and behavioral states. , 1978, Science.

[14]  D. McCreery,et al.  Histological evaluation of neural damage from electrical stimulation: considerations for the selection of parameters for clinical application. , 1981, Neurosurgery.

[15]  B. Rockstroh,et al.  The influence of low-level transcortical DC-currents on response speed in humans. , 1981, The International journal of neuroscience.

[16]  Korsakov Ia,et al.  Psychophysical characteristics of perception and of brain electrical activity during occipital micropolarization. , 1982 .

[17]  E. Bienenstock,et al.  Theory for the development of neuron selectivity: orientation specificity and binocular interaction in visual cortex , 1982, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[18]  I A Korsakov,et al.  Psychophysical characteristics of perception and of brain electrical activity during occipital micropolarization. , 1982, Human physiology.

[19]  R. Buijs,et al.  Light and electron microscopic immunocytochemical analysis of the serotonin innervation of the rat visual cortex , 1987, Journal of neurocytology.

[20]  D B McCreery,et al.  Considerations for safety in the use of extracranial stimulation for motor evoked potentials. , 1987, Neurosurgery.

[21]  T. O'donohue,et al.  Glycine modulation of the phencyclidine binding site in mammalian brain , 1988, Brain Research.

[22]  P. Schönle,et al.  Changes of transcranially evoked motor responses in man by midazolam, a short acting benzodiazepine , 1989, Neuroscience Letters.

[23]  Yasuo Hori,et al.  Biphasic effects of polarizing current on adenosine-sensitive generation of cyclic AMP in rat cerebral cortex , 1990, Neuroscience Letters.

[24]  C. Scholfield Properties of K-currents in unmyelinated presynaptic axons of brain revealed by extracellular polarisation , 1990, Brain Research.

[25]  C. Scholfield Properties of K-currents in unmyelinated presynaptic axons of brain revealed revealed by extracellular polarisation. , 1990, Brain research.

[26]  P. Goldman-Rakic,et al.  Autoradiographic comparison of D1-specific binding of [3H]SCH39166 and SCH23390 in the primate cerebral cortex , 1990, Brain Research.

[27]  P. Kalivas,et al.  Amphetamine lowers extracellular GABA concentration in the ventral pallidum , 1990, Brain Research.

[28]  J. DeFelipe,et al.  Synaptic relationships of serotonin-immunoreactive terminal baskets on GABA neurons in the cat auditory cortex. , 1991, Cerebral cortex.

[29]  KM Jacobs,et al.  Reshaping the cortical motor map by unmasking latent intracortical connections , 1991, Science.

[30]  A. Kelley,et al.  NMDA receptors mediate the behavioral effects of amphetamine infused into the nucleus accumbens , 1992, Brain Research Bulletin.

[31]  W. Singer,et al.  Agonists of cholinergic and noradrenergic receptors facilitate synergistically the induction of long-term potentiation in slices of rat visual cortex , 1992, Brain Research.

[32]  C. Marsden,et al.  Corticocortical inhibition in human motor cortex. , 1993, The Journal of physiology.

[33]  R. Yasuda,et al.  Development of antisera selective for m4 and m5 muscarinic cholinergic receptors: distribution of m4 and m5 receptors in rat brain. , 1993, Molecular pharmacology.

[34]  P. Pflimlin,et al.  Dextromethorphan blocks N-methyl-D-aspartate-induced currents and voltage-operated inward currents in cultured cortical neurons. , 1993, European journal of pharmacology.

[35]  David A. Smith,et al.  Temporal covariance of pre- and postsynaptic activity regulates functional connectivity in the visual cortex. , 1994, Journal of neurophysiology.

[36]  J. Donoghue,et al.  Long-term potentiation of horizontal connections provides a mechanism to reorganize cortical motor maps. , 1994, Journal of neurophysiology.

[37]  Yun-fei Lu,et al.  c-Fos Expression Mediated by N-Methyl-d-aspartate Receptors Following Anodal Polarization in the Rat Brain , 1995, Experimental Neurology.

[38]  J. Donoghue,et al.  Different forms of synaptic plasticity in somatosensory and motor areas of the neocortex , 1995, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[39]  R. Karler,et al.  The dopaminergic, glutamatergic, GABAergic bases for the action of amphetamine and cocaine , 1995, Brain Research.

[40]  A. Keller,et al.  Mechanisms of LTP induction in rat motor cortex in vitro. , 1995, Cerebral cortex.

[41]  Y. Frégnac,et al.  Temporal constraints in associative synaptic plasticity in hippocampus and neocortex. , 1995, Canadian journal of physiology and pharmacology.

[42]  Yasuo Hori,et al.  Increase in the calcium level following anodal polarization in the rat brain , 1995, Brain Research.

[43]  Walter Paulus,et al.  Enhancement of human motor cortex inhibition by the dopamine receptor agonist pergolide: evidence from transcranial magnetic stimulation , 1996, Neuroscience Letters.

[44]  J. Donoghue,et al.  Conditions for the induction of long-term potentiation in layer II/III horizontal connections of the rat motor cortex. , 1996, Journal of neurophysiology.

[45]  J. Rothwell,et al.  Interaction between intracortical inhibition and facilitation in human motor cortex. , 1996, The Journal of physiology.

[46]  M. Bear,et al.  Experience-dependent modification of synaptic plasticity in visual cortex , 1996, Nature.

[47]  T. Jay,et al.  Plasticity of the hippocampal-prefrontal cortex synapses , 1996, Journal of Physiology-Paris.

[48]  J. Donoghue,et al.  Long-term potentiation and long-term depression of horizontal connections in rat motor cortex. , 1996, Acta neurobiologiae experimentalis.

[49]  M. Kossut,et al.  Neonatal serotonin depletion modifies development but not plasticity in rat barrel cortex , 1997, Neuroreport.

[50]  M. Okada,et al.  Determination of the effects of caffeine and carbamazepine on striatal dopamine release by in vivo microdialysis. , 1997, European journal of pharmacology.

[51]  M. Cynader,et al.  Serotonin facilitates synaptic plasticity in kitten visual cortex: an in vitro study. , 1997, Brain research. Developmental brain research.

[52]  G. W. Huntley,et al.  Correlation between patterns of horizontal connectivity and the extend of short-term representational plasticity in rat motor cortex. , 1997, Cerebral cortex.

[53]  H. Alkadhi,et al.  Localization of the motor hand area to a knob on the precentral gyrus. A new landmark. , 1997, Brain : a journal of neurology.

[54]  V. Sethy,et al.  D1 dopamine receptor activity of anti-parkinsonian drugs. , 1997, Life sciences.

[55]  J. Desce,et al.  Dopamine facilitates long-term depression of glutamatergic transmission in rat prefrontal cortex , 1998, Neuroscience.

[56]  K. Abe,et al.  5-HT1A receptor-mediated inhibition of long-term potentiation in rat visual cortex. , 1998, European journal of pharmacology.

[57]  K. Abe,et al.  Serotonin inhibits the induction of long-term potentiation in rat primary visual cortex , 1998, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[58]  R. Racine,et al.  Long-term potentiation in the neocortex of the adult, freely moving rat. , 1998, Cerebral cortex.

[59]  N Accornero,et al.  Polarization of the human motor cortex through the scalp , 1998, Neuroreport.

[60]  J. Donoghue,et al.  Strengthening of horizontal cortical connections following skill learning , 1998, Nature Neuroscience.

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

[62]  M. Bear,et al.  Modulation of Long-Term Synaptic Depression in Visual Cortex by Acetylcholine and Norepinephrine , 1999, The Journal of Neuroscience.

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

[64]  B. Bunney,et al.  Opposite modulation of cortical N-methyl-d-aspartate receptor-mediated responses by low and high concentrations of dopamine , 1999, Neuroscience.

[65]  J. Donoghue,et al.  Facilitation of long-term potentiation in layer II/III horizontal connections of rat motor cortex following layer I stimulation: route of effect and cholinergic contributions , 1999, Experimental Brain Research.

[66]  K. Abe,et al.  Stimulation of the 5-HT1A receptor selectively suppresses NMDA receptor-mediated synaptic excitation in the rat visual cortex , 1999, Brain Research.

[67]  R. Racine,et al.  GABAergic modulation of neocortical long‐term potentiation in the freely moving rat , 2000, Synapse.

[68]  M. Okada,et al.  Effects of carbamazepine on acetylcholine release and metabolism , 2000, Epilepsy Research.

[69]  T. Jay,et al.  Essential Role of D1 But Not D2 Receptors in the NMDA Receptor-Dependent Long-Term Potentiation at Hippocampal-Prefrontal Cortex Synapses In Vivo , 2000, The Journal of Neuroscience.

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

[71]  M. Nitsche,et al.  Excitability changes induced in the human motor cortex by weak transcranial direct current stimulation , 2000, The Journal of physiology.

[72]  Walter Paulus,et al.  Diminution of training-induced transient motor cortex plasticity by weak transcranial direct current stimulation in the human , 2000, Neuroscience Letters.

[73]  W. Fischer,et al.  Riluzole suppresses motor cortex facilitation in correlation to its plasma level , 2000, Experimental Brain Research.

[74]  M. Nitsche,et al.  Sustained excitability elevations induced by transcranial DC motor cortex stimulation in humans , 2001, Neurology.

[75]  L. Cohen,et al.  Mechanisms influencing stimulus-response properties of the human corticospinal system , 2001, Clinical Neurophysiology.

[76]  D. Ji,et al.  Timing and Location of Nicotinic Activity Enhances or Depresses Hippocampal Synaptic Plasticity , 2001, Neuron.

[77]  P. O’Donnell,et al.  D(1) dopamine receptors potentiate nmda-mediated excitability increase in layer V prefrontal cortical pyramidal neurons. , 2001, Cerebral cortex.

[78]  S. Floresco,et al.  Delay-dependent modulation of memory retrieval by infusion of a dopamine D1 agonist into the rat medial prefrontal cortex. , 2001, Behavioral neuroscience.

[79]  J E Lisman,et al.  Three Ca2+ levels affect plasticity differently: the LTP zone, the LTD zone and no man's land , 2001, The Journal of physiology.

[80]  M. Yoshioka,et al.  Changes in synaptic plasticity in the rat hippocampo-medial prefrontal cortex pathway induced by repeated treatments with fluvoxamine , 2002, Brain Research.

[81]  Q. Gu,et al.  Neuromodulatory transmitter systems in the cortex and their role in cortical plasticity , 2002, Neuroscience.

[82]  Diane Ruge,et al.  Short‐interval paired‐pulse inhibition and facilitation of human motor cortex: the dimension of stimulus intensity , 2002, The Journal of physiology.

[83]  M. Nitsche,et al.  Pharmacological approach to the mechanisms of transcranial DC-stimulation-induced after-effects of human motor cortex excitability. , 2002, Brain : a journal of neurology.

[84]  Satoru Otani,et al.  Long-term potentiation in rat prefrontal slices facilitated by phased application of dopamine. , 2002, European journal of pharmacology.

[85]  M. Nitsche,et al.  Facilitation of Implicit Motor Learning by Weak Transcranial Direct Current Stimulation of the Primary Motor Cortex in the Human , 2003, Journal of Cognitive Neuroscience.

[86]  J. Rothwell,et al.  Level of action of cathodal DC polarisation induced inhibition of the human motor cortex , 2003, Clinical Neurophysiology.

[87]  Walter Paulus,et al.  Modulation of motor consolidation by external DC stimulation. , 2003, Supplements to Clinical neurophysiology.

[88]  M. Nitsche,et al.  Pharmacological Modulation of Cortical Excitability Shifts Induced by Transcranial Direct Current Stimulation in Humans , 2003, The Journal of physiology.

[89]  S. Kourrich,et al.  NMDA receptor-dependent long-term synaptic depression in the entorhinal cortex in vitro. , 2003, Journal of neurophysiology.

[90]  A. Priori Brain polarization in humans: a reappraisal of an old tool for prolonged non-invasive modulation of brain excitability , 2003, Clinical Neurophysiology.

[91]  Ulf Ziemann,et al.  The α2-adrenergic agonist guanfacine reduces excitability of human motor cortex through disfacilitation and increase of inhibition , 2003, Clinical Neurophysiology.

[92]  Walter Paulus,et al.  Modulation of cortical excitability by weak direct current stimulation--technical, safety and functional aspects. , 2003, Supplements to Clinical neurophysiology.

[93]  D. Liebetanz,et al.  MRI study of human brain exposed to weak direct current stimulation of the frontal cortex , 2004, Clinical Neurophysiology.

[94]  J. Seamans,et al.  The principal features and mechanisms of dopamine modulation in the prefrontal cortex , 2004, Progress in Neurobiology.

[95]  M. Bear,et al.  LTP and LTD An Embarrassment of Riches , 2004, Neuron.

[96]  Y. Takeuchi,et al.  Immunohistochemical demonstration of serotonin nerve fibers in the neocortex of the monkey (Macaca fuscata) , 2004, Anatomy and Embryology.

[97]  R. Racine,et al.  N-methyl-d-aspartate receptor-independent long-term depression and depotentiation in the sensorimotor cortex of the freely moving rat , 2004, Neuroscience.

[98]  M. Nitsche,et al.  GABAergic modulation of DC stimulation‐induced motor cortex excitability shifts in humans , 2004, The European journal of neuroscience.

[99]  T. Bliss,et al.  Long-Term Potentiation: Enhancing Neuroscience for 30 Years , 2004 .

[100]  J. Rothwell,et al.  Preconditioning with transcranial direct current stimulation sensitizes the motor cortex to rapid-rate transcranial magnetic stimulation and controls the direction of after-effects , 2004, Biological Psychiatry.

[101]  Walter Paulus,et al.  Consolidation of Human Motor Cortical Neuroplasticity by D-Cycloserine , 2004, Neuropsychopharmacology.

[102]  Walter Paulus,et al.  Catecholaminergic consolidation of motor cortical neuroplasticity in humans. , 2004, Cerebral cortex.

[103]  P. Andersen,et al.  Mode of activation of hippocampal pyramidal cells by excitatory synapses on dendrites , 2004, Experimental Brain Research.

[104]  Y. Takeuchi,et al.  Serotonin nerve fibers in the primary visual cortex of the monkey , 1984, Anatomy and Embryology.

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

[106]  A. Berardelli,et al.  Effects of diazepam, baclofen and thiopental on the silent period evoked by transcranial magnetic stimulation in humans , 1996, Experimental Brain Research.

[107]  André Parent,et al.  Giovanni Aldini: From Animal Electricity to Human Brain Stimulation , 2004, Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques.

[108]  S. Sato,et al.  Safety and cognitive effect of frontal DC brain polarization in healthy individuals , 2005, Neurology.

[109]  Sergio P. Rigonatti,et al.  Transcranial direct current stimulation of the unaffected hemisphere in stroke patients , 2005, Neuroreport.

[110]  A. Priori,et al.  Non‐synaptic mechanisms underlie the after‐effects of cathodal transcutaneous direct current stimulation of the human brain , 2005, The Journal of physiology.

[111]  L. Cohen,et al.  Effects of non-invasive cortical stimulation on skilled motor function in chronic stroke. , 2005, Brain : a journal of neurology.

[112]  S. Ge,et al.  Nicotinic Acetylcholine Receptors at Glutamate Synapses Facilitate Long-Term Depression or Potentiation , 2005, The Journal of Neuroscience.

[113]  M. Nitsche,et al.  Modulating parameters of excitability during and after transcranial direct current stimulation of the human motor cortex , 2005, Clinical Neurophysiology.

[114]  U. Ziemann,et al.  Modification of motor cortical excitability by an acetylcholinesterase inhibitor , 2005, Experimental Brain Research.

[115]  A. Oliviero,et al.  Effects of lorazepam on short latency afferent inhibition and short latency intracortical inhibition in humans , 2005, The Journal of physiology.

[116]  Sergio P. Rigonatti,et al.  A sham-controlled, phase II trial of transcranial direct current stimulation for the treatment of central pain in traumatic spinal cord injury , 2006, PAIN.

[117]  M. Nitsche,et al.  After-effects of transcranial direct current stimulation (tDCS) on cortical spreading depression , 2006, Neuroscience Letters.

[118]  Sergio P. Rigonatti,et al.  Enhancement of non-dominant hand motor function by anodal transcranial direct current stimulation , 2006, Neuroscience Letters.

[119]  S. Härtter,et al.  A review of the receptor-binding and pharmacokinetic properties of dopamine agonists. , 2006, Clinical therapeutics.

[120]  U. Ziemann,et al.  TMS-assisted neurophysiological profiling of the dopamine receptor agonist cabergoline in human motor cortex , 2007, Journal of Neural Transmission.

[121]  M. Hallett,et al.  Modeling the current distribution during transcranial direct current stimulation , 2006, Clinical Neurophysiology.

[122]  Walter Paulus,et al.  Dopaminergic modulation of long‐lasting direct current‐induced cortical excitability changes in the human motor cortex , 2006 .

[123]  Sergio P. Rigonatti,et al.  A randomized, sham-controlled, proof of principle study of transcranial direct current stimulation for the treatment of pain in fibromyalgia. , 2006, Arthritis and rheumatism.

[124]  Á. Pascual-Leone,et al.  A Controlled Clinical Trial of Cathodal DC Polarization in Patients with Refractory Epilepsy , 2006, Epilepsia.

[125]  Sergio P. Rigonatti,et al.  Repeated sessions of noninvasive brain DC stimulation is associated with motor function improvement in stroke patients. , 2007, Restorative neurology and neuroscience.

[126]  M. Nitsche,et al.  Shaping the effects of transcranial direct current stimulation of the human motor cortex. , 2007, Journal of neurophysiology.

[127]  Markus Zahn,et al.  Transcranial direct current stimulation: A computer-based human model study , 2007, NeuroImage.

[128]  Marie-H Monfils,et al.  Induction of neocortical long-term depression results in smaller movement representations, fewer excitatory perforated synapses, and more inhibitory synapses. , 2006, Cerebral cortex.

[129]  Walter Paulus,et al.  Focusing Effect of Acetylcholine on Neuroplasticity in the Human Motor Cortex , 2007, The Journal of Neuroscience.

[130]  A. Antal,et al.  Safety aspects of transcranial direct current stimulation concerning healthy subjects and patients , 2007, Brain Research Bulletin.

[131]  M. Nitsche,et al.  Prior state of cortical activity influences subsequent practicing of a visuomotor coordination task , 2008, Neuropsychologia.

[132]  Á. Pascual-Leone,et al.  A randomized, double-blind clinical trial on the efficacy of cortical direct current stimulation for the treatment of major depression. , 2008, The international journal of neuropsychopharmacology.

[133]  M. Nitsche,et al.  Boosting focally-induced brain plasticity by dopamine. , 2008, Cerebral cortex.

[134]  Ulf Ziemann Pharmacology of TMS measures , 2008 .

[135]  Daniel A Bloch,et al.  A preliminary randomized, double-blind, placebo-controlled study of the safety and efficacy of ondansetron in the treatment of methamphetamine dependence. , 2008, The international journal of neuropsychopharmacology.

[136]  Gottfried Schlaug,et al.  Dual-hemisphere tDCS facilitates greater improvements for healthy subjects' non-dominant hand compared to uni-hemisphere stimulation , 2008, BMC Neuroscience.

[137]  Á. Pascual-Leone,et al.  Cortical stimulation of the prefrontal cortex with transcranial direct current stimulation reduces cue-provoked smoking craving: a randomized, sham-controlled study. , 2008, The Journal of clinical psychiatry.

[138]  M. Nitsche,et al.  Limited impact of homeostatic plasticity on motor learning in humans , 2008, Neuropsychologia.

[139]  L. Cohen,et al.  Transcranial direct current stimulation: State of the art 2008 , 2008, Brain Stimulation.

[140]  M. Nitsche,et al.  Safety limits of cathodal transcranial direct current stimulation in rats , 2009, Clinical Neurophysiology.

[141]  Ethan R. Buch,et al.  Noninvasive cortical stimulation enhances motor skill acquisition over multiple days through an effect on consolidation , 2009, Proceedings of the National Academy of Sciences.

[142]  Pablo Celnik,et al.  Brain polarization enhances the formation and retention of motor memories. , 2009, Journal of neurophysiology.

[143]  Paul Sacco,et al.  Modulation of internal model formation during force field‐induced motor learning by anodal transcranial direct current stimulation of primary motor cortex , 2009, The Journal of physiology.

[144]  P. Matthews,et al.  Polarity-Sensitive Modulation of Cortical Neurotransmitters by Transcranial Stimulation , 2009, The Journal of Neuroscience.

[145]  Walter Paulus,et al.  Serotonin affects transcranial direct current-induced neuroplasticity in humans , 2009 .

[146]  M. Nitsche,et al.  D1-Receptor Impact on Neuroplasticity in Humans , 2009, The Journal of Neuroscience.

[147]  Walter Paulus,et al.  Dose-Dependent Inverted U-Shaped Effect of Dopamine (D2-Like) Receptor Activation on Focal and Nonfocal Plasticity in Humans , 2009, The Journal of Neuroscience.

[148]  C. Epstein,et al.  The Oxford handbook of transcranial stimulation , 2012 .