Rehabilitating the addicted brain with transcranial magnetic stimulation

Abstract

Substance use disorders (SUDs) are one of the leading causes of morbidity and mortality worldwide. In spite of considerable advances in understanding the neural underpinnings of SUDs, therapeutic options remain limited. Recent studies have highlighted the potential of transcranial magnetic stimulation (TMS) as an innovative, safe and cost-effective treatment for some SUDs. Repetitive TMS (rTMS) influences neural activity in the short and long term by mechanisms involving neuroplasticity both locally, under the stimulating coil, and at the network level, throughout the brain. The long-term neurophysiological changes induced by rTMS have the potential to affect behaviours relating to drug craving, intake and relapse. Here, we review TMS mechanisms and evidence that rTMS is opening new avenues in addiction treatments.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: TMS physiology.
Figure 2: Brain stimulation mechanisms in animal and human models of addiction.

References

  1. 1

    Koob, G. & Volkow, N. Neurocircuitry of addiction. Neuropsychopharmacology 35, 217–238 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  2. 2

    Chen, B. et al. Rescuing cocaine-induced prefrontal cortex hypoactivity prevents compulsive cocaine seeking. Nature 496, 359–362 (2013).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  3. 3

    Levy, D. et al. Repeated electrical stimulation of reward-related brain regions affects cocaine but not “natural” reinforcement. J. Neurosci. 27, 14179–14189 (2007).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  4. 4

    Melis, M., Spiga, S. & Diana, M. The dopamine hypothesis of drug addiction: hypodopaminergic state. Int. Rev. Neurobiol. 63, 101–154 (2005).

    CAS  Article  Google Scholar 

  5. 5

    Strafella, A., Paus, T., Barrett, J. & Dagher, A. Repetitive transcranial magnetic stimulation of the human prefrontal cortex induces dopamine release in the caudate nucleus. J Neurosci. 21, RC157 (2001).

    CAS  Article  Google Scholar 

  6. 6

    Barker, A., Jalinous, R. & Freeston, I. Non-invasive magnetic stimulation of human motor cortex. Lancet 1, 1106–1107 (1985).

    CAS  Article  Google Scholar 

  7. 7

    Terao, Y. & Ugawa, Y. Basic mechanisms of TMS. J. Clin. Neurophysiol. 19, 322–343 (2002).

    Article  Google Scholar 

  8. 8

    Di Lazzaro, V., Ziemann, U. & Lemon, R. State of the art: physiology of transcranial motor cortex stimulation. Brain Stimul. 1, 345–362 (2008).

    Article  Google Scholar 

  9. 9

    Rossi, S., Hallett, M., Rossini, P. M., & Pascual-Leone, A. Safety, ethical considerations, and application guidelines for the use of transcranial magnetic stimulation in clinical practice and research. Clin. Neurophysiol. 120, 2008–2039 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  10. 10

    Huang, Y.-Z., Edwards, M., Rounis, E., Bhatia, K. & Rothwell, J. Theta burst stimulation of the human motor cortex. Neuron 45, 201–206 (2005).

    CAS  Article  Google Scholar 

  11. 11

    Hamada, M. et al. Quadro-pulse stimulation is more effective than paired-pulse stimulation for plasticity induction of the human motor cortex. Clin. Neurophysiol. 118, 2672–2682 (2007).

    Article  Google Scholar 

  12. 12

    Pascual-Leone, A., Valls-Sole, J., Wassermann, E. & Hallett, M. Responses to rapid-rate transcranial magnetic stimulation of the human motor cortex. Brain 117, 847–858 (1994).

    Article  Google Scholar 

  13. 13

    Chen, R. et al. Depression of motor cortex excitability by low-frequency transcranial magnetic stimulation. Neurology 48, 1398–1403 (1997).

    CAS  Article  Google Scholar 

  14. 14

    Silvanto, J. & Pascual-Leone, A. State-dependency of transcranial magnetic stimulation. Brain Topogr. 21, 1–10 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  15. 15

    Silvanto, J., Cattaneo, Z., Battelli, L. & Pascual-Leone, A. Baseline cortical excitability determines whether TMS disrupts or facilitates behavior. J. Neurophysiol. 99, 2725–2730 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  16. 16

    Ilmoniemi, R. et al. Neuronal responses to magnetic stimulation reveal cortical reactivity and connectivity. Neuroreport 8, 3537–3540 (1997).

    CAS  Article  Google Scholar 

  17. 17

    Paus, T. et al. Transcranial magnetic stimulation during positron emission tomography: a new method for studying connectivity of the human cerebral cortex. J. Neurosci. 17, 3178–3184 (1997).

    CAS  Article  Google Scholar 

  18. 18

    Bohning, D. et al. Echoplanar BOLD fMRI of brain activation induced by concurrent transcranial magnetic stimulation. Invest. Radiol. 33, 336–340 (1998).

    CAS  Article  Google Scholar 

  19. 19

    Bestmann, S., Baudewig, J., Siebner, H., Rothwell, J. & Frahm, J. Functional MRI of the immediate impact of transcranial magnetic stimulation on cortical and subcortical motor circuits. Eur. J. Neurosci. 19, 1950–1962 (2004).

    Article  Google Scholar 

  20. 20

    Radman, T., Ramos, R., Brumberg, J. & Bikson, M. Role of cortical cell type and morphology in subthreshold and suprathreshold uniform electric field stimulation in vitro. Brain Stimul. 2, 215–228 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  21. 21

    Pashut, T. et al. Patch-clamp recordings of rat neurons from acute brain slices of the somatosensory cortex during magnetic stimulation. Front. Cell Neurosci. 8, 145 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. 22

    Edgley, S., Eyre, J., Lemon, R. & Miller, S. Comparison of activation of corticospinal neurons and spinal motor neurons by magnetic and electrical transcranial stimulation in the lumbosacral cord of the anaesthetized monkey. Brain 120, 839–853 (1997).

    Article  Google Scholar 

  23. 23

    Mueller, J. et al. Simultaneous transcranial magnetic stimulation and single-neuron recording in alert non-human primates. Nat. Neurosci. 17, 1130–1136 (2014).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  24. 24

    Cohen, D. & Cuffin, B. Developing a more focal magnetic stimulator. Part I: some basic principles. J. Clin. Neurophysiol. 8, 102–111 (1991).

    CAS  Article  Google Scholar 

  25. 25

    Ilmoniemi, R., Ruohonen, J. & Karhu, J. Transcranial magnetic stimulation — a new tool for functional imaging of the brain. Crit. Rev. Biomed. Eng. 27, 241–284 (1999).

    CAS  PubMed  Google Scholar 

  26. 26

    Miranda, P., Hallett, M. & Basser, P. The electric field induced in the brain by magnetic stimulation: a 3D finite-element analysis of the effect of tissue heterogeneity and anisotropy. IEEE Trans. Biomed. Eng. 50, 1074–1085 (2003).

    Article  Google Scholar 

  27. 27

    Silva, S., Basser, P. & Miranda, P. Elucidating the mechanisms and loci of neuronal excitation by transcranial magnetic stimulation using a finite element model of a cortical sulcus. Clin. Neurophysiol. 119, 2405–2413 (2008).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  28. 28

    Salinas, F., Lancaster, J. & Fox, P. 3D modeling of the total electric field induced by transcranial magnetic stimulation using the boundary element method. Phys. Med. Biol. 54, 3631–3647 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  29. 29

    Salvador, R., Silva, S., Basser, P. & Miranda, P. Determining which mechanisms lead to activation in the motor cortex: a modeling study of transcranial magnetic stimulation using realistic stimulus waveforms and sulcal geometry. Clin. Neurophysiol. 122, 748–758 (2011).

    CAS  Article  Google Scholar 

  30. 30

    Opitz, A., Windhoff, M., Heidemann, R., Turner, R. & Thielscher, A. How the brain tissue shapes the electric field induced by transcranial magnetic stimulation. Neuroimage 58, 849–859 (2011).

    Article  Google Scholar 

  31. 31

    Opitz, A., Zafar, N., Bockermann, V., Rohde, V. & Paulus, W. Validating computationally predicted TMS stimulation areas using direct electrical stimulation in patients with brain tumors near precentral regions. Neuroimage Clin. 4, 500–507 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  32. 32

    Nummenmaa, A. et al. Comparison of spherical and anatomically realistic boundary element head models for transcranial magnetic stimulation navigation. Clin. Neurophysiol. 124, 1995–2007 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  33. 33

    Nummenmaa, A. et al. Targeting of white matter tracts with transcranial magnetic stimulation. Brain Stimul. 7, 80–84 (2014).

    Article  Google Scholar 

  34. 34

    Ziemann, U. TMS and drugs. Clin. Neurophysiol. 115, 1717–1729 (2004).

    CAS  Article  Google Scholar 

  35. 35

    Paulus, W. et al. State of the art: pharmacologic effects on cortical excitability measures tested by transcranial magnetic stimulation. Brain Stimul. 1, 151–163 (2008).

    Article  Google Scholar 

  36. 36

    Ziemann, U. et al. TMS and drugs revisited 2014. Clin. Neurophysiol. 126, 1847–1868 (2015).

    Article  Google Scholar 

  37. 37

    Fox, P. et al. Imaging intra-cerebral connectivity by PET during TMS. Neuroreport 8, 2787–2791 (1997).

    CAS  Article  Google Scholar 

  38. 38

    Di Lazzaro, V. et al. I-Wave origin and modulation. Brain Stimul. 5, 512–525 (2012).

    CAS  Article  Google Scholar 

  39. 39

    Niehaus, L., Meyer, B. & Weyh, T. Influence of pulse configuration and direction of coil current on excitatory effects of magnetic motor cortex and nerve stimulation. Clin. Neurophysiol. 111, 75–80 (2000).

    CAS  Article  Google Scholar 

  40. 40

    Peterchev, A., Goetz, S., Westin, G., Luber, B. & Lisanby, S. Pulse width dependence of motor threshold and input-output curve characterized with controllable pulse parameter transcranial magnetic stimulation. Clin. Neurophysiol. 124, 1364–1372 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  41. 41

    Rushton, W. The effect upon the threshold for nervous excitation of the length of nerve exposed, and the angle between current and nerve. J. Physiol. 63, 357–377 (1927).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  42. 42

    Amassian, V., Eberle, L., Maccabee, P. & Cracco, R. Modelling magnetic coil excitation of human cerebral cortex with a peripheral nerve immersed in a brain-shaped volume conductor: the significance of fiber bending in excitation. Electroencephalogr. Clin. Neurophysiol. 85, 291–301 (1992).

    CAS  Article  Google Scholar 

  43. 43

    Roth, B. Mechanisms for electrical stimulation of excitable tissue. Crit. Rev. Biomed. Eng. 22, 253–305 (1994).

    CAS  PubMed  Google Scholar 

  44. 44

    Maccabee, P., Amassian, V., Eberle, L. & Cracco, R. Magnetic coil stimulation of straight and bent amphibian and mammalian peripheral nerve in vitro: locus of excitation. J. Physiol. 460, 201–219 (1993).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  45. 45

    Nagarajan, S., Durand, D. & Warman, E. Effects of induced electric fields on finite neuronal structures: a simulation study. IEEE Trans. Biomed. Eng. 40, 1175–1188 (1993).

    CAS  Article  Google Scholar 

  46. 46

    D'Ostilio, K. et al. Effect of coil orientation on strength-duration time constant and I-wave activation with controllable pulse parameter transcranial magnetic stimulation. Clin. Neurophysiol. 127, 675–683 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  47. 47

    Patton, H. & Amassian, V. Single and multiple-unit analysis of cortical stage of pyramidal tract activation. J. Neurophysiol. 17, 345–363 (1954).

    CAS  Article  Google Scholar 

  48. 48

    Valls-Sole, J., Pascual-Leone, A., Wassermann, E. & Hallett, M. Human motor evoked responses to paired transcranial magnetic stimuli. Electroencephalogr. Clin. Neurophysiol. 85, 355–364 (1992).

    CAS  Article  Google Scholar 

  49. 49

    McDonnell, M., Orekhov, Y. & Ziemann, U. The role of GABA(B) receptors in intracortical inhibition in the human motor cortex. Exp. Brain Res. 173, 86–93 (2006).

    CAS  Article  Google Scholar 

  50. 50

    Romero, J., Anschel, D., Sparing, R., Gangitano, M. & Pascual-Leone, A. Subthreshold low frequency repetitive transcranial magnetic stimulation selectively decreases facilitation in the motor cortex. Clin. Neurophysiol. 113, 101–107 (2002).

    Article  Google Scholar 

  51. 51

    Maeda, F., Keenan, J., Tormos, J., Topka, H. & Pascual-Leone, A. Modulation of corticospinal excitability by repetitive transcranial magnetic stimulation. Clin. Neurophysiol. 111, 800–805 (2000).

    CAS  Article  Google Scholar 

  52. 52

    Ridding, M. & Ziemann, U. Determinants of the induction of cortical plasticity by non-invasive brain stimulation in healthy subjects. J. Physiol. 588, 2291–2304 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  53. 53

    Vernet, M. et al. Reproducibility of the effects of theta burst stimulation on motor cortical plasticity in healthy participants. Clin. Neurophysiol. 125, 320–326 (2014).

    Article  Google Scholar 

  54. 54

    Hamada, M., Murase, N., Hasan, A., Balaratnam, M. & Rothwell, J. The role of interneuron networks in driving human motor cortical plasticity. Cereb. Cortex 23, 1593–1605 (2013).

    Article  Google Scholar 

  55. 55

    Strafella, A., Paus, T., Fraraccio, M. & Dagher, A. Striatal dopamine release induced by repetitive transcranial magnetic stimulation of the human motor cortex. Brain 126, 2609–2615 (2003).

    Article  Google Scholar 

  56. 56

    Cho, S. & Strafella, A. rTMS of the left dorsolateral prefrontal cortex modulates dopamine release in the ipsilateral anterior cingulate cortex and orbitofrontal cortex. PLoS ONE 4, e6725 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. 57

    Baeken, C. et al. The impact of HF-rTMS treatment on serotonin(2A) receptors in unipolar melancholic depression. Brain Stimul. 4, 104–111 (2011).

    Article  Google Scholar 

  58. 58

    Baeken, C. & De Raedt, R. Neurobiological mechanisms of repetitive transcranial magnetic stimulation on the underlying neurocircuitry in unipolar depression. Dialogues Clin. Neurosci. 13, 139–145 (2011).

    PubMed  PubMed Central  Google Scholar 

  59. 59

    Bashir, S., Edwards, D. & Pascual-Leone, A. Neuronavigation increases the physiologic and behavioral effects of low-frequency rTMS of primary motor cortex in healthy subjects. Brain Topogr. 24, 54–64 (2011).

    CAS  Article  Google Scholar 

  60. 60

    Plewnia, C., Lotze, M. & Gerloff, C. Disinhibition of the contralateral motor cortex by low-frequency rTMS. Neuroreport 14, 609–612 (2003).

    Article  Google Scholar 

  61. 61

    Schambra, H., Sawaki, L. & Cohen, L. Modulation of excitability of human motor cortex (M1) by 1 Hz transcranial magnetic stimulation of the contralateral M1. Clin. Neurophysiol. 114, 130–133 (2003).

    CAS  Article  Google Scholar 

  62. 62

    Suppa, A. et al. Theta burst stimulation induces after-effects on contralateral primary motor cortex excitability in humans. J. Physiol. 586, 4489–4500 (2008).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  63. 63

    Di Lazzaro, V. et al. The physiological basis of the effects of intermittent theta burst stimulation of the human motor cortex. J. Physiol. 586, 3871–3879 (2008).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  64. 64

    Vlachos, A. et al. Repetitive magnetic stimulation induces functional and structural plasticity of excitatory postsynapses in mouse organotypic hippocampal slice cultures. J. Neurosci. 32, 17514–17523 (2012).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  65. 65

    Lenz, M. et al. Repetitive magnetic stimulation induces plasticity of excitatory postsynapses on proximal dendrites of cultured mouse CA1 pyramidal neurons. Brain Struct. Funct. 220, 3323–3337 (2015).

    CAS  Article  Google Scholar 

  66. 66

    Müller-Dahlhaus, F., Ziemann, U. & Classen, J. Plasticity resembling spike-timing dependent synaptic plasticity: the evidence in human cortex. Front. Synapt. Neurosci. 2, 34 (2010).

    Google Scholar 

  67. 67

    Daskalakis, Z. et al. The effects of repetitive transcranial magnetic stimulation on cortical inhibition in healthy human subjects. Exp. Brain Res. 174, 403–412 (2006).

    Article  Google Scholar 

  68. 68

    Barr, M., Farzan, F., Davis, K., Fitzgerald, P. & Daskalakis, Z. Measuring GABAergic inhibitory activity with TMS-EEG and its potential clinical application for chronic pain. J. Neuroimmune Pharmacol. 8, 535–546 (2013).

    Article  Google Scholar 

  69. 69

    Lenz, M. et al. Repetitive magnetic stimulation induces plasticity of inhibitory synapses. Nat. Commun. 7, 10020 (2016).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  70. 70

    Normann, C. et al. Associative long-term depression in the hippocampus is dependent on postsynaptic N-type Ca2+ channels. J. Neurosci. 20, 8290–8297 (2000).

    CAS  Article  Google Scholar 

  71. 71

    Raymond, C. Different requirements for action potentials in the induction of different forms of long-term potentiation. J. Physiol. 586, 1859–1865 (2008).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  72. 72

    Ziemann, U. et al. Consensus: motor cortex plasticity protocols. Brain Stimul. 1, 164–182 (2008).

    Article  Google Scholar 

  73. 73

    Hoogendam, J., Ramakers, G. & Di Lazzaro, V. Physiology of repetitive transcranial magnetic stimulation of the human brain. Brain Stimul. 3, 95–118 (2010).

    Article  Google Scholar 

  74. 74

    Tang, A., Thickbroom, G. & Rodger, J. Repetitive transcranial magnetic stimulation of the brain: mechanisms from animal and experimental models. Neuroscientist 23, 82–94 (2015).

    Article  Google Scholar 

  75. 75

    Fitzgerald, P., Fountain, S. & Daskalakis, Z. A comprehensive review of the effects of rTMS on motor cortical excitability and inhibition. Clin. Neurophysiol. 117, 2584–2596 (2006).

    Article  Google Scholar 

  76. 76

    Müller-Dahlhaus, F. & Vlachos, A. Unraveling the cellular and molecular mechanisms of repetitive magnetic stimulation. Front. Mol. Neurosci. 6, 50 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. 77

    Pell, G., Roth, Y. & Zangen, A. Modulation of cortical excitability induced by repetitive transcranial magnetic stimulation: influence of timing and geometrical parameters and underlying mechanisms. Prog. Neurobiol. 93, 59–98 (2010).

    Article  Google Scholar 

  78. 78

    Funke, K. & Benali, A. Modulation of cortical inhibition by rTMS — findings obtained from animal models. J. Physiol. 589, 4423–4435 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  79. 79

    Banerjee, J., Sorrell, M., Celnik, P. & Pelled, G. Immediate effects of repetitive magnetic stimulation on single cortical pyramidal neurons. PLoS ONE 12, e0170528 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. 80

    Yang, S., Tang, Y. & Zucker, R. Selective induction of LTP and LTD by postsynaptic [Ca2+]i elevation. J. Neurophysiol. 81, 781–787 (1999).

    CAS  Article  Google Scholar 

  81. 81

    Murphy, S., Palmer, L., Nyffeler, T., Müri, R. & Larkum, M. Transcranial magnetic stimulation (TMS) inhibits cortical dendrites. Elife 5, e13598 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  82. 82

    Tigaret, C., Olivo, V., Sadowski, J., Ashby, M. & Mellor, J. Coordinated activation of distinct Ca2+ sources and metabotropic glutamate receptors encodes Hebbian synaptic plasticity. Nat. Commun. 7, 10289 (2016).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  83. 83

    Zanardini, R. et al. Effect of repetitive transcranial magnetic stimulation on serum brain derived neurotrophic factor in drug resistant depressed patients. J. Affect. Disord. 91, 83–86 (2006).

    CAS  Article  Google Scholar 

  84. 84

    Cheeran, B. et al. A common polymorphism in the brain-derived neurotrophic factor gene (BDNF) modulates human cortical plasticity and the response to rTMS. J. Physiol. 586, 5717–5725 (2008).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  85. 85

    Chen, J. et al. Heterosynaptic long-term depression mediated by ATP released from astrocytes. Glia 61, 178–191 (2013).

    Article  Google Scholar 

  86. 86

    Letellier, M. et al. Astrocytes regulate heterogeneity of presynaptic strengths in hippocampal networks. Proc. Natl Acad. Sci. USA 113, E2685–E2694 (2016).

    CAS  Article  Google Scholar 

  87. 87

    Etiévant, A. et al. Repetitive transcranial magnetic stimulation induces long-lasting changes in protein expression and histone acetylation. Sci. Rep. 5, 16873 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. 88

    Ceccanti, M. et al. Deep TMS on alcoholics: effects on cortisolemia and dopamine pathway modulation. A pilot study. Can. J. Physiol. Pharmacol. 93, 283–290 (2015).

    CAS  Article  Google Scholar 

  89. 89

    Löffler, S. et al. The effect of repetitive transcranial magnetic stimulation on monoamine outflow in the nucleus accumbens shell in freely moving rats. Neuropharmacology 63, 898–904 (2012).

    Article  CAS  Google Scholar 

  90. 90

    Keck, M. et al. Repetitive transcranial magnetic stimulation increases the release of dopamine in the mesolimbic and mesostriatal system. Neuropharmacology 43, 101–109 (2002).

    CAS  Article  Google Scholar 

  91. 91

    Zangen, A. & Hyodo, K. Transcranial magnetic stimulation induces increases in extracellular levels of dopamine and glutamate in the nucleus accumbens. Neuroreport 13, 2401–2405 (2002).

    CAS  Article  Google Scholar 

  92. 92

    Ikemoto, S. & Bonci, A. Neurocircuitry of drug reward. Neuropharmacology 76, 329–341 (2014).

    CAS  Article  Google Scholar 

  93. 93

    Baik, J. Dopamine signaling in reward-related behaviors. Front. Neural Circuits 7, 152 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. 94

    Volman, S. et al. New insights into the specificity and plasticity of reward and aversion encoding in the mesolimbic system. J. Neurosci. 33, 17569–17576 (2013).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  95. 95

    Pignatelli, M. & Bonci, A. Role of dopamine neurons in reward and aversion: a synaptic plasticity perspective. Neuron 86, 1145–1157 (2015).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  96. 96

    Diana, M. The dopamine hypothesis of drug addiction and its potential therapeutic value. Front. Psychiatry 2, 64 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  97. 97

    Lüscher, C. The emergence of a circuit model for addiction. Annu. Rev. Neurosci. 39, 257–276 (2016).

    Article  CAS  Google Scholar 

  98. 98

    Argilli, E., Sibley, D., Malenka, R., England, P. & Bonci, A. Mechanism and time course of cocaine-induced long-term potentiation in the ventral tegmental area. J. Neurosci. 28, 9092–9100 (2008).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  99. 99

    Bellone, C. & Lüscher, C. Cocaine triggered AMPA receptor redistribution is reversed in vivo by mGluR-dependent long-term depression. Nat. Neurosci. 9, 636–641 (2006).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  100. 100

    Chen, B. et al. Cocaine but not natural reward self-administration nor passive cocaine infusion produces persistent LTP in the VTA. Neuron 59, 288–297 (2008).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  101. 101

    Good, C. & Lupica, C. Afferent-specific AMPA receptor subunit composition and regulation of synaptic plasticity in midbrain dopamine neurons by abused drugs. J. Neurosci. 30, 7900–7909 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  102. 102

    Mameli, M., Balland, B., Luján, R. & Lüscher, C. Rapid synthesis and synaptic insertion of GluR2 for mGluR-LTD in the ventral tegmental area. Science 317, 530–533 (2007).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  103. 103

    Saal, D., Dong, Y., Bonci, A. & Malenka, R. Drugs of abuse and stress trigger a common synaptic adaptation in dopamine neurons. Neuron 37, 577–582 (2003).

    CAS  Article  Google Scholar 

  104. 104

    Ungless, M., Whistler, J., Malenka, R. & Bonci, A. Single cocaine exposure in vivo induces long-term potentiation in dopamine neurons. Nature 411, 583–587 (2001).

    CAS  Article  Google Scholar 

  105. 105

    Bock, R. et al. Strengthening the accumbal indirect pathway promotes resilience to compulsive cocaine use. Nat. Neurosci. 16, 632–638 (2013).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  106. 106

    Hsiang, H. et al. Manipulating a “cocaine engram” in mice. J. Neurosci. 34, 14115–14127 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. 107

    Kasanetz, F. et al. Transition to addiction is associated with a persistent impairment in synaptic plasticity. Science 328, 1709–1712 (2010).

    CAS  Article  Google Scholar 

  108. 108

    Kasanetz, F. et al. Prefrontal synaptic markers of cocaine addiction-like behavior in rats. Mol. Psychiatry 18, 729–737 (2013).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  109. 109

    Volkow, N., Wang, G. & Fowler, J. Imaging studies of cocaine in the human brain and studies of the cocaine addict. Ann. N. Y. Acad. Sci. 820, 41–54 (1997).

    CAS  Article  Google Scholar 

  110. 110

    Volkow, N., Koob, G. & McLellan, A. Neurobiologic advances from the brain disease model of addiction. N. Engl. J. Med. 374, 363–371 (2016).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  111. 111

    Wiers, C., Cabrera, E., Skarda, E., Volkow, N. & Wang, G. PET imaging for addiction medicine: from neural mechanisms to clinical considerations. Prog. Brain Res. 224, 175–201 (2016).

    Article  Google Scholar 

  112. 112

    Hatzigiakoumis, D., Martinotti, G., Giannantonio, M. & Janiri, L. Anhedonia and substance dependence: clinical correlates and treatment options. Front. Psychiatry 2, 10 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  113. 113

    Stein, D. & Manyedi, E. Psychoactive substances: position statement on harm reduction. S. Afr. Med. J. 106, 11223 (2016).

    PubMed  Google Scholar 

  114. 114

    George, O., Koob, G. & Vendruscolo, L. Negative reinforcement via motivational withdrawal is the driving force behind the transition to addiction. Psychopharmacology (Berl.) 231, 3911–3917 (2014).

    CAS  Article  Google Scholar 

  115. 115

    Koob, G. & Le Moal, M. Plasticity of reward neurocircuitry and the 'dark side' of drug addiction. Nat. Neurosci. 8, 1442–1444 (2005).

    CAS  Article  Google Scholar 

  116. 116

    Yagishita, S. et al. A critical time window for dopamine actions on the structural plasticity of dendritic spines. Science 345, 1616–1620 (2014).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  117. 117

    Dan, Y. & Poo, M. Spike timing-dependent plasticity: from synapse to perception. Physiol. Rev. 86, 1033–1048 (2006).

    Article  Google Scholar 

  118. 118

    Spiga, S. et al. Hampered long-term depression and thin spine loss in the nucleus accumbens of ethanol-dependent rats. Proc. Natl Acad. Sci. USA 111, E3745–3754 (2014).

    CAS  Article  Google Scholar 

  119. 119

    Kasai, H., Matsuzaki, M., Noguchi, J., Yasumatsu, N. & Nakahara, H. Structure-stability-function relationships of dendritic spines. Trends Neurosci. 26, 360–368 (2003).

    CAS  Article  Google Scholar 

  120. 120

    Freund, T., Powell, J. & Smith, A. Tyrosine hydroxylase-immunoreactive boutons in synaptic contact with identified striatonigral neurons, with particular reference to dendritic spines. Neuroscience 13, 1189–1215 (1984).

    CAS  Article  Google Scholar 

  121. 121

    Terraneo, A. et al. Transcranial magnetic stimulation of dorsolateral prefrontal cortex reduces cocaine use: a pilot study. Eur. Neuropsychopharmacol. 26, 37–44 (2016).

    CAS  Article  Google Scholar 

  122. 122

    Politi, E., Fauci, E., Santoro, A. & Smeraldi, E. Daily sessions of transcranial magnetic stimulation to the left prefrontal cortex gradually reduce cocaine craving. Am. J. Addict. 17, 345–346 (2008).

    Article  Google Scholar 

  123. 123

    Rapinesi, C. et al. Add-on high frequency deep transcranial magnetic stimulation (dTMS) to bilateral prefrontal cortex reduces cocaine craving in patients with cocaine use disorder. Neurosci. Lett. 629, 43–47 (2016).

    CAS  Article  Google Scholar 

  124. 124

    Bolloni, C. et al. Bilateral transcranial magnetic stimulation of the prefrontal cortex reduces cocaine intake: a pilot study. Front. Psychiatry 7, 133 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  125. 125

    Keck, M. et al. Acute transcranial magnetic stimulation of frontal brain regions selectively modulates the release of vasopressin, biogenic amines and amino acids in the rat brain. Eur. J. Neurosci. 12, 3713–3720 (2000).

    CAS  Article  Google Scholar 

  126. 126

    Deng, Z., Lisanby, S. & Peterchev, A. Electric field depth-focality tradeoff in transcranial magnetic stimulation: simulation comparison of 50 coil designs. Brain Stimul. 6, 1–13 (2013).

    Article  Google Scholar 

  127. 127

    Addolorato, G. et al. Deep transcranial magnetic stimulation of the dorsolateral prefrontal cortex in alcohol use disorder patients: effects on dopamine transporter availability and alcohol intake. Eur. Neuropsychopharmacol. 27, 450–461 (2017).

    CAS  Article  Google Scholar 

  128. 128

    Dinur-Klein, L. et al. Smoking cessation induced by deep repetitive transcranial magnetic stimulation of the prefrontal and insular cortices: a prospective, randomized controlled trial. Biol. Psychiatry 76, 742–749 (2014).

    Article  Google Scholar 

  129. 129

    Alger, B. Endocannabinoid signaling in neural plasticity. Curr. Top. Behav. Neurosci. 1, 141–172 (2009).

    CAS  Article  Google Scholar 

  130. 130

    Castillo, P., Younts, T., Chávez, A. & Hashimotodani, Y. Endocannabinoid signaling and synaptic function. Neuron 76, 70–81 (2012).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  131. 131

    Iremonger, K., Wamsteeker Cusulin, J. & Bains, J. Changing the tune: plasticity and adaptation of retrograde signals. Trends Neurosci. 36, 471–479 (2013).

    CAS  Article  Google Scholar 

  132. 132

    Abraham, W. Metaplasticity: tuning synapses and networks for plasticity. Nat. Rev. Neurosci. 9, 387 (2008).

    CAS  Article  Google Scholar 

  133. 133

    Camprodon, J., Martínez-Raga, J., Alonso-Alonso, M., Shih, M. & Pascual-Leone, A. One session of high frequency repetitive transcranial magnetic stimulation (rTMS) to the right prefrontal cortex transiently reduces cocaine craving. Drug Alcohol Depend. 86, 91–94 (2007).

    Article  Google Scholar 

  134. 134

    Mishra, B., Praharaj, S., Katshu, M., Sarkar, S. & Nizamie, S. Comparison of anticraving efficacy of right and left repetitive transcranial magnetic stimulation in alcohol dependence: a randomized double-blind study. J. Neuropsychiatry Clin. Neurosci. 27, e54–e59 (2015).

    Article  Google Scholar 

  135. 135

    Toga, A. & Thompson, P. Mapping brain asymmetry. Nat. Rev. Neurosci. 4, 37–48 (2003).

    CAS  Article  Google Scholar 

  136. 136

    Trouche, S. et al. Recoding a cocaine-place memory engram to a neutral engram in the hippocampus. Nat. Neurosci. 19, 564–567 (2016).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  137. 137

    Corbit, L., Nie, H. & Janak, P. Habitual responding for alcohol depends upon both AMPA and D2 receptor signaling in the dorsolateral striatum. Front. Behav. Neurosci. 8, 301 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. 138

    Kling, J., Yarita, M., Yamamoto, T. & Matsumiya, Y. Memory for conditioned taste aversions is diminished by transcranial magnetic stimulation. Physiol. Behav. 48, 713–717 (1990).

    CAS  Article  Google Scholar 

  139. 139

    Valero-Cabré, A., Pascual-Leone, A. & Rushmore, R. Cumulative sessions of repetitive transcranial magnetic stimulation (rTMS) build up facilitation to subsequent TMS-mediated behavioural disruptions. Eur. J. Neurosci. 27, 765–774 (2008).

    Article  Google Scholar 

  140. 140

    Cash, R., Murakami, T., Chen, R., Thickbroom, G. & Ziemann, U. Augmenting plasticity induction in human motor cortex by disinhibition stimulation. Cereb. Cortex 26, 58–69 (2016).

    Article  Google Scholar 

  141. 141

    Sewerin, S. et al. Enhancing the effect of repetitive I-wave paired-pulse TMS (iTMS) by adjusting for the individual I-wave periodicity. BMC Neurosci. 12, 45 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  142. 142

    Zrenner, C., Belardinelli, P., Müller-Dahlhaus, F. & Ziemann, U. Closed-loop neuroscience and non-invasive brain stimulation: a tale of two loops. Front. Cell Neurosci. 10, 92 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  143. 143

    Fox, M., Liu, H. & Pascual-Leone, A. Identification of reproducible individualized targets for treatment of depression with TMS based on intrinsic connectivity. Neuroimage 66, 151–160 (2013).

    Article  Google Scholar 

  144. 144

    Hanlon, C., Dowdle, L. & Jones, J. Biomarkers for success: using neuroimaging to predict relapse and develop brain stimulation treatments for cocaine-dependent individuals. Int. Rev. Neurobiol. 129, 125–156 (2016).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  145. 145

    Luber, B. et al. Using neuroimaging to individualize TMS treatment for depression: toward a new paradigm for imaging-guided intervention. Neuroimage 148, 1–7 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  146. 146

    Ruohonen, J. & Karhu, J. Navigated transcranial magnetic stimulation. Neurophysiol. Clin. 40, 7–17 (2010).

    CAS  Article  Google Scholar 

  147. 147

    Ahveninen, J. et al. Evidence for distinct human auditory cortex regions for sound location versus identity processing. Nat. Comm. 4, 2585 (2013).

    Article  CAS  Google Scholar 

  148. 148

    Fox, M., Buckner, R., White, M., Greicius, M. & Pascual-Leone, A. Efficacy of transcranial magnetic stimulation targets for depression is related to intrinsic functional connectivity with the subgenual cingulate. Biol. Psychiatry 72, 595–603 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  149. 149

    Fattore, L. & Diana, M. Drug addiction: an affective-cognitive disorder in need of a cure. Neurosci. Biobehav. Rev. 65, 341–361 (2016).

    Article  Google Scholar 

  150. 150

    Davey, K., Epstein, C., George, M. & Bohning, D. Modeling the effects of electrical conductivity of the head on the induced electric field in the brain during magnetic stimulation. Clin. Neurophysiol. 114, 2204–2209 (2003).

    Article  Google Scholar 

  151. 151

    Wagner, T., Zahn, M., Grodzinsky, A. & Pascual-Leone, A. Three-dimensional head model simulation of transcranial magnetic stimulation. IEEE Trans. Biomed. Eng. 51, 1586–1598 (2004).

    Article  Google Scholar 

  152. 152

    Chen, M. & Mogul, D. Using increased structural detail of the cortex to improve the accuracy of modeling the effects of transcranial magnetic stimulation on neocortical activation. IEEE Trans. Biomed. Eng. 57, 1216–1226 (2010).

    Article  Google Scholar 

  153. 153

    Opitz, A. et al. Physiological observations validate finite element models for estimating subject-specific electric field distributions induced by transcranial magnetic stimulation of the human motor cortex. Neuroimage 81, 253–264 (2013).

    Article  Google Scholar 

  154. 154

    Deng, Z., Lisanby, S. & Peterchev, A. Coil design considerations for deep transcranial magnetic stimulation. Clin. Neurophysiol. 125, 1202–1212 (2014).

    Article  Google Scholar 

  155. 155

    Yunokuchi, K. & Cohen, D. Developing a more focal magnetic stimulator. Part II: Fabricating coils and measuring induced current distributions. J. Clin. Neurophysiol. 8, 112–120 (1991).

    CAS  Article  Google Scholar 

  156. 156

    Brasil-Neto, J. et al. Optimal focal transcranial magnetic activation of the human motor cortex: effects of coil orientation, shape of the induced current pulse, and stimulus intensity. J. Clin. Neurophysiol. 9, 132–136 (1992).

    CAS  Article  Google Scholar 

  157. 157

    Pascual-Leone, A., Cohen, L., Brasil-Neto, J. & Hallett, M. Non-invasive differentiation of motor cortical representation of hand muscles by mapping of optimal current directions. Electroencephalogr. Clin. Neurophysiol. 93, 42–48 (1994).

    CAS  Article  Google Scholar 

  158. 158

    Werhahn, K. et al. The effect of magnetic coil orientation on the latency of surface EMG and single motor unit responses in the first dorsal interosseous muscle. Electroencephalogr. Clin. Neurophysiol. 93, 138–146 (1994).

    CAS  Article  Google Scholar 

  159. 159

    Day, B. et al. Electric and magnetic stimulation of human motor cortex: surface EMG and single motor unit responses. J. Physiol. 412, 449–473 (1989).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  160. 160

    Amassian, V., Quirk, G. J. & Stewart, M. A comparison of corticospinal activation by magnetic coil and electrical stimulation of monkey motor cortex. Electro-encephalogr. Clin. Neurophysiol. 77, 390–401 (1990).

    CAS  Article  Google Scholar 

  161. 161

    Wilson, S., Day, B., Thickbroom, G. & Mastaglia, F. Spatial differences in the sites of direct and indirect activation of corticospinal neurones by magnetic stimulation. Electroencephalogr. Clin. Neurophysiol. 101, 255–261 (1996).

    CAS  Article  Google Scholar 

  162. 162

    Nakamura, H., Kitagawa, H., Kawaguchi, Y. & Tsuji, H. Direct and indirect activation of human corticospinal neurons by transcranial magnetic and electrical stimulation. Neurosci. Lett. 210, 45–48 (1996).

    CAS  Article  Google Scholar 

  163. 163

    Di Lazzaro, V. et al. Comparison of descending volleys evoked by transcranial magnetic and electric stimulation in conscious humans. Electroencephalogr. Clin. Neurophysiol. 109, 397–401 (1998).

    CAS  Article  Google Scholar 

  164. 164

    Di Lazzaro, V. & Ziemann, U. The contribution of transcranial magnetic stimulation in the functional evaluation of microcircuits in human motor cortex. Front. Neural Circuits 7, 18 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  165. 165

    Mountcastle, V. Perceptual Neuroscience: The Cerebral Cortex (Harvard Univ. Press, 1998).

    Google Scholar 

  166. 166

    Goldstein, R. & Volkow, N. Dysfunction of the prefrontal cortex in addiction: neuroimaging findings and clinical implications. Nat. Rev. Neurosci. 12, 652–669 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  167. 167

    Ferenczi, E. & Deisseroth, K. Illuminating next-generation brain therapies. Nat. Neurosci. 19, 414–416 (2016).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  168. 168

    Kujirai, T. et al. Corticocortical inhibition in human motor cortex. J. Physiol. 471, 501–519 (1993).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  169. 169

    Ziemann, U., Rothwell, J. & Ridding, M. Interaction between intracortical inhibition and facilitation in human motor cortex. J. Physiol. 496, 873–881 (1996).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  170. 170

    Di Lazzaro, V. et al. Direct demonstration of the effect of lorazepam on the excitability of the human motor cortex. Clin. Neurophysiol. 111, 794–799 (2000).

    CAS  Article  Google Scholar 

  171. 171

    Tokimura, H., Ridding, M., Tokimura, Y., Amassian, V. & Rothwell, J. Short latency facilitation between pairs of threshold magnetic stimuli applied to human motor cortex. Electroencephalogr. Clin. Neurophysiol. 101, 263–272 (1996).

    CAS  Article  Google Scholar 

  172. 172

    Ilic, T. et al. Short-interval paired-pulse inhibition and facilitation of human motor cortex: the dimension of stimulus intensity. J. Physiol. 545, 153–167 (2002).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  173. 173

    Ziemann, U. et al. Demonstration of facilitatory I wave interaction in the human motor cortex by paired transcranial magnetic stimulation. J. Physiol. 511, 181–190 (1998).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  174. 174

    Hanajima, R. et al. Mechanisms of intracortical I-wave facilitation elicited with paired-pulse magnetic stimulation in humans. J. Physiol. 538, 253–261 (2002).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  175. 175

    Claus, D., Weis, M., Jahnke, U., Plewe, A. & Brunhölzl, C. Corticospinal conduction studied with magnetic double stimulation in the intact human. J. Neurol. Sci. 111, 180–188 (1992).

    CAS  Article  Google Scholar 

  176. 176

    Hamada, M. et al. Bidirectional long-term motor cortical plasticity and metaplasticity induced by quadripulse transcranial magnetic stimulation. J. Physiol. 586, 3927–3947 (2008).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  177. 177

    Khedr, E., Gilio, F. & Rothwell, J. Effects of low frequency and low intensity repetitive paired pulse stimulation of the primary motor cortex. Clin. Neurophysiol. 115, 1259–1263 (2004).

    Article  Google Scholar 

  178. 178

    Thickbroom, G., Byrnes, M., Edwards, D. & Mastaglia, F. Repetitive paired-pulse TMS at I-wave periodicity markedly increases corticospinal excitability: a new technique for modulating synaptic plasticity. Clin. Neurophysiol. 117, 61–66 (2006).

    Article  Google Scholar 

  179. 179

    Hamada, M. et al. Origin of facilitation in repetitive, 1.5 ms interval, paired pulse transcranial magnetic stimulation (rPPS) of the human motor cortex. Clin. Neurophysiol. 118, 1596–1601 (2007).

    Article  Google Scholar 

  180. 180

    Fitzgerald, P. et al. A comparative study of the effects of repetitive paired transcranial magnetic stimulation on motor cortical excitability. J. Neurosci. Methods 165, 265–269 (2007).

    Article  Google Scholar 

Download references

Acknowledgements

Supported by the US National Institute on Drug Abuse Intramural Research Program (A.B., L.L.), the Division of Intramural Clinical and Biological Research of the National Institute on Alcohol Abuse and Alcoholism (L.L.), the University of Sassari Department of Antidrug Policies and the Ministero dell'Istruzione dell'Università e della Ricerca (MIUR) (M.D.), the Dr Ralph and Marian Falk Medical Research Trust and NIH grants R01MH106512 and S10OD020080 (T.R.) and NIH grants R00EB015445 and R01MH111829 (A.N.). The content of this article is solely the responsibility of the authors and does not necessarily represent the official views of the NIH or other funding organizations.

Author information

Affiliations

Authors

Contributions

A.B. made substantial contribution to discussion of content and reviewed or edited the manuscript before submission.

M D., T.R., M.M. A.N. and L.L. contributed to the writing of the manuscript.

Corresponding author

Correspondence to Antonello Bonci.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

PowerPoint slides

Glossary

Conventional rTMS

A form of TMS sequences where the pulses are given at regular intervals (for example, 1 Hz or 20 Hz).

Direct mechanism

(D-mechanism). A mechanism in TMS in which the pyramidal neurons are directly activated by the TMS-induced E-fields.

Electric field

(E-field). The field induced by the TMS coil. When the E-field interacts with a conducting medium, this drives electric currents.

Indirect mechanism

(I-mechanism). A mechanism in TMS in which the pyramidal neurons are activated trans-synaptically, that is, indirectly.

Motor threshold

(MT). The minimum TMS intensity that must be applied to the motor cortex to induce a peripheral muscle contraction.

Quadripulse stimulation

(QPS). A form of patterned TMS where the TMS pulses are arranged in more complex patterns than in conventional rTMS.

Repetitive paired-pulse TMS

(rppTMS). A form of patterned TMS where the TMS pulses are arranged in more complex patterns than in conventional rTMS.

Repetitive TMS

(rTMS). A form of TMS in which individual TMS pulses are presented at regular time intervals (for example, 1 Hz, 20 Hz). Also known as 'conventional rTMS'.

Theta burst stimulation

(TBS). A form of patterned TMS where the TMS pulses are arranged in more complex patterns than in conventional rTMS.

TMS navigator

A device that enables accurate tracking of the TMS coil position relative to the subject's head. Often integrated with MRI of the subject's head.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Diana, M., Raij, T., Melis, M. et al. Rehabilitating the addicted brain with transcranial magnetic stimulation. Nat Rev Neurosci 18, 685–693 (2017). https://doi.org/10.1038/nrn.2017.113

Download citation

Further reading