Ischemic cerebral stroke is the leading cause of long-term disability among adults in industrialized countries. One fundamental but still not sufficiently solved question is how to improve disability after stroke. Here, evidence will be reviewed on how pharmacological treatment modulates plasticity and learning in the intact human motor cortex. It will be argued that these data may be useful for advancing the concepts of pharmacotherapy for recovery after stroke.
Dobkin BH.Clinical practice. Rehabilitation after stroke. N Engl J Med2005;352(16):1677-1684.
2.
Gresham GE, Fitzpatrick TE, Wolf PA, McNamara PM, Kannel WB, Dawber TR.Residual disability in survivors of stroke—the Framingham study. N Engl J Med1975;293(19):954-956.
3.
Liebeskind DS, Kasner SE.Neuroprotection for ischaemic stroke: an unattainable goal?CNS Drugs2001;15(3):165-174.
4.
Goldstein LB.Restorative neurology. Advances in pharmacotherapy for recovery after stroke. Armonk, NY: Futura; 1998.
5.
Weiller C.Imaging recovery from stroke. Exp Brain Res1998; 123(1-2):13-17.
6.
Liepert J.TMS in stroke. Suppl Clin Neurophysiol2003;56:368-380.
7.
Rossini PM, Liepert J.Lesions of cortex and post-stroke “plastic” reorganization. In: Boniface SJ, Ziemann U, eds. Plasticity in the human nervous system. Investigations with transcranial magnetic stimulation. Cambridge, UK: Cambridge University Press; 2003: 166-203.
8.
Dobkin BH.Neurobiology of rehabilitation. Ann N Y Acad Sci2004;1038:148-170.
9.
Ward NS, Cohen LG.Mechanisms underlying recovery of motor function after stroke. Arch Neurol2004;61(12):1844-1848.
10.
Ward NS.Neural plasticity and recovery of function. Prog Brain Res2005;150:527-535.
11.
Ziemann U.Improving disability in stroke with RTMS. Lancet Neurol2005;4(8):454-455.
12.
Kaas JH.Plasticity of sensory and motor maps in adult mammals. Annu Rev Neurosci1991;14:137-167.
13.
Weinberger NM.Dynamic regulation of receptive fields and maps in the adult sensory cortex. Annu Rev Neurosci1995;18:129-158.
14.
Bliss TV, Collingridge GL.A synaptic model of memory: long-term potentiation in the hippocampus. Nature1993;361 (6407):31-39.
15.
Markram H, Lubke J, Frotscher M, Sakmann B.Regulation of synaptic efficacy by coincidence of postsynaptic APs and EPSPs. Science1997;275(5297):213-215.
16.
Baranyi A, Feher O.Synaptic facilitation requires paired activation of convergent pathways in the neocortex. Nature1981;290 (5805):413-415.
17.
Iriki A, Pavlides C, Keller A, Asanuma H.Long-term potentiation in the motor cortex. Science1989;245(4924):1385-1387.
18.
Kimura A, Grigor’yan R, Asanuma H.Long-term increases in neuronal activity in the motor cortex evoked by simultaneous stimulation of the thalamus and somatosensory cortex in cats. Neurosci Behav Physiol1999;29(4):475-481.
19.
Asanuma H, Keller A.Neuronal mechanisms of motor learning in mammals. Neuroreport1991;2(5):217-224.
20.
Donoghue JP, Hess G, Sanes JN.Substrates and mechanisms for learning in motor cortex. In: Bloedel J, Ebner T, Wise SP, eds. Acquisition of motor behavior in vertebrates. Cambridge, MA: MIT Press; 1996:363-386.
21.
Sanes JN, Donoghue JP.Plasticity and primary motor cortex. Annu Rev Neurosci2000;23:393-415.
22.
Aroniadou VA, Keller A.Mechanisms of LTP induction in rat motor cortex in vitro. Cereb Cortex1995;5(4):353-362.
23.
Castro-Alamancos MA, Donoghue JP, Connors BW.Different forms of synaptic plasticity in somatosensory and motor areas of the neocortex. J Neurosci1995;15(7 Pt 2):5324-5333.
24.
Hess G, Aizenman CD, Donoghue JP.Conditions for the induction of long-term potentiation in layer II/III horizontal connections of the rat motor cortex. J Neurophysiol1996;75(5):1765-1778.
25.
Jacobs KM, Donoghue JP.Reshaping the cortical motor map by unmasking latent intracortical connections. Science1991;251 (4996):944-947.
26.
Hess G, Donoghue JP.Long-term potentiation of horizontal connections provides a mechanism to reorganize cortical motor maps. J Neurophysiol1994;71(6):2543-2547.
27.
Hagemann G, Redecker C, Neumann-Haefelin T, Freund H-J, Witte O.Increased long-term potentiation in the surround of experimentally induced focal cortical infarction. Ann Neurol1998;44:255-258.
28.
Trepel C, Racine RJ.GABAergic modulation of neocortical long-term potentiation in the freely moving rat. Synapse2000;35 (2):120-128.
29.
Gu Q.Neuromodulatory transmitter systems in the cortex and their role in cortical plasticity. Neuroscience2002;111(4):815-835.
30.
Hess G, Donoghue JP.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. Exp Brain Res1999;127:279-290.
31.
Chen R, Classen J, Gerloff C, et al.Depression of motor cortex excitability by low-frequency transcranial magnetic stimulation. Neurology1997;48:1398-1403.
32.
Ziemann U, Corwell B, Cohen LG.Modulation of plasticity in human motor cortex after forearm ischemic nerve block. J Neurosci1998;18(3):1115-1123.
33.
Ziemann U, Hallett M, Cohen LG.Mechanisms of deafferentation-induced plasticity in human motor cortex. J Neurosci1998;18(17):7000-7007.
34.
Maeda F, Keenan JP, Tormos JM, Topka H, Pascual-Leone A.Interindividual variability of the modulatory effects of repetitive transcranial magnetic stimulation on cortical excitability. Exp Brain Res2000;133(4):425-430.
35.
Stefan K, Kunesch E, Cohen LG, Benecke R, Classen J.Induction of plasticity in the human motor cortex by paired associative stimulation. Brain2000;123(Pt 3):572-584.
36.
Ridding MC, Taylor JL.Mechanisms of motor-evoked potential facilitation following prolonged dual peripheral and central stimulation in humans. J Physiol2001;537(Pt 2):623-631.
37.
Classen J, Ziemann U.Stimulation-induced plasticity in the human motor cortex. In: Boniface SJ, Ziemann U, eds. Plasticity in the human nervous system. Investigation with transcranial magnetic stimulation. Cambridge, UK: Cambridge University Press; 2003:135-165.
38.
Classen J, Wolters A, Stefan K, et al.Paired associative stimulation. Suppl Clin Neurophysiol2004;57:563-569.
39.
Peinemann A, Reimer B, Loer C, et al.Long-lasting increase in corticospinal excitability after 1800 pulses of subthreshold 5 Hz repetitive TMS to the primary motor cortex. Clin Neurophysiol2004;115(7):1519-1526.
40.
Ziemann U.TMS induced plasticity in human cortex. Rev Neurosci2004;15(4):252-266.
41.
Huang Y-Z, Edwards MJ, Rounis E, Bhatia KP, Rothwell JC.Theta burst stimulation of the human motor cortex. Neuron2005;45 (2):201-206.
42.
Thickbroom GW, Byrnes ML, Edwards DJ, Mastaglia FL.Repetitive paired-pulse TMS at I-wave periodicity markedly increases corticospinal excitability: a new technique for modulating synaptic plasticity. Clin Neurophysiol2006;117:61-66.
43.
Barker AT, Jalinous R, Freeston IL.Non-invasive magnetic stimulation of human motor cortex [letter]. Lancet1985;1(8437):1106-1107.
44.
Hallett M.Transcranial magnetic stimulation and the human brain. Nature2000;406(6792):147-150.
45.
Levy L, Ziemann U, Chen R, Cohen LG.Rapid modulation of GABA in sensorimotor cortex induced by acute deafferentation. Ann Neurol2002;52(6):755-761.
46.
Stefan K, Kunesch E, Benecke R, Cohen LG, Classen J.Mechanisms of enhancement of human motor cortex excitability induced by interventional paired associative stimulation. J Physiol2002;543(Pt 2):699-708.
47.
Wolters A, Sandbrink F, Schlottmann A, et al.A temporally asymmetric Hebbian rule governing plasticity in the human motor cortex. J Neurophysiol2003;89(5):2339-2345.
48.
Ziemann U, Ilic TV, Pauli C, Meintzschel F, Ruge D.Learning modifies subsequent induction of LTP-like and LTD-like plasticity in human motor cortex. J Neurosci2004;24(7):1666-1672.
49.
Stefan K, Wycislo M, Gentner R, et al.Temporary occlusion of associative motor cortical plasticity by prior dynamic motor training. Cereb Cortex2006;16(3):376-385.
50.
Korchounov A, Ilic TV, Ziemann U.Modulation LTP-ähnlicher Plastizität im Motorkortex des Menschen durch Monoamine und Acetylcholin [Abstract]. Aktuelle Neurologie2002;29(Suppl 2): S107-8.
51.
Rioult-Pedotti M-S, Friedman D, Hess G, Donoghue JP.Strengthening of horizontal cortical connections following skill learning. Nature Neurosci1998;1(3):230-234.
52.
Rioult-Pedotti MS, Friedman D, Donoghue JP.Learning-induced LTP in neocortex. Science2000;290(5491):533-536.
53.
Monfils MH, Teskey GC.Skilled-learning-induced potentiation in rat sensorimotor cortex: a transient form of behavioural long-term potentiation. Neuroscience2004;125(2):329-336.
54.
Hodgson RA, Ji Z, Standish S, Boyd-Hodgson TE, Henderson AK, Racine RJ.Training-induced and electrically induced potentiation in the neocortex. Neurobiol Learn Mem2005;83(1): 22-32.
55.
Bütefisch C, Hummelsheim H, Denzler P, Mauritz K-H.Repetitive training of isolated movements improves the outcome of motor rehabilitation of the centrally paretic hand. J Neurol Sci1995;130(1):59-68.
56.
Woldag H, Hummelsheim H.Evidence-based physiotherapeutic concepts for improving arm and hand function in stroke patients: a review. J Neurol2002;249(5):518-528.
57.
Nudo RJ, Milliken GW, Jenkins WM, Merzenich MM.Use-dependent alterations of movement representations in primary motor cortex of adult squirrel monkeys. J Neurosci1996;16(2): 785-807.
58.
Kleim JA, Barbay S, Nudo RJ.Functional reorganization of the rat motor cortex following motor skill learning. J Neurophysiol1998;80(6):3321-3325.
59.
Remple MS, Bruneau RM, VandenBerg PM, Goertzen C, Kleim JA.Sensitivity of cortical movement representations to motor experience: evidence that skill learning but not strength training induces cortical reorganization. Behav Brain Res2001;123(2):133-141.
60.
Cain DP.Testing the NMDA, long-term potentiation, and cholinergic hypotheses of spatial learning. Neurosci Biobehav Rev1998;22(2):181-193.
61.
Conner JM, Culberson A, Packowski C, Chiba AA, Tuszynski MH.Lesions of the Basal forebrain cholinergic system impair task acquisition and abolish cortical plasticity associated with motor skill learning. Neuron2003;38(5):819-829.
62.
Pascual-Leone A, Nguyet D, Cohen LG, Brasil-Neto JP, Cammarota A, Hallett M.Modulation of muscle responses evoked by transcranial magnetic stimulation during the acquisition of new fine motor skills. J Neurophysiol1995;74(3):1037-1045.
63.
Classen J, Liepert J, Wise SP, Hallett M, Cohen LG.Rapid plasticity of human cortical movement representation induced by practice. J Neurophysiol1998;79(2):1117-1123.
64.
Liepert J, Terborg C, Weiller C.Motor plasticity induced by synchronized thumb and foot movements. Exp Brain Res1999; 125(4):435-439.
65.
Pearce AJ, Thickbroom GW, Byrnes ML, Mastaglia FL.Functional reorganisation of the corticomotor projection to the hand in skilled racquet players. Exp Brain Res2000;130(2):238-243.
66.
Svensson P, Romaniello A, Arendt-Nielsen L, Sessle BJ.Plasticity in corticomotor control of the human tongue musculature induced by tongue-task training. Exp Brain Res2003;152(1):42-51.
67.
Classen J, Cohen LG.Practice-induced plasticity in the human motor cortex. In: Boniface SJ, Ziemann U, eds. Plasticity in the human nervous system. Investigations with transcranial magnetic stimulation. Cambridge, UK: Cambridge University Press; 2003:90-106.
68.
Tyc F, Boyadjian A, Devanne H.Motor cortex plasticity induced by extensive training revealed by transcranial magnetic stimulation in human. Eur J Neurosci2005;21:259-266.
69.
Muellbacher W, Ziemann U, Boroojerdi B, Cohen LG, Hallett M.Role of the human motor cortex in rapid motor learning. Exp Brain Res2001;136(4):431-438.
70.
Muellbacher W, Ziemann U, Wissel J, et al.Early consolidation in human primary motor cortex. Nature2002;415:640-644.
71.
Ziemann U, Muellbacher W, Hallett M, Cohen LG.Modulation of practice-dependent plasticity in human motor cortex. Brain2001;124(6):1171-1181.
72.
Sohn YH, Jung HY, Kaelin-Lang A, Hallett M.Effect of levetiracetam on rapid motor learning in humans. Arch Neurol2002;59(12):1909-1912.
73.
Bütefisch CM, Davis BC, Wise SP, et al.Mechanisms of use-dependent plasticity in the human motor cortex. Proc Natl Acad Sci U S A2000;97(7):3661-3665.
74.
Flöel A, Breitenstein C, Hummel F, et al.Dopaminergic influences on formation of a motor memory. Ann Neurol2005;58(1):121-130.
75.
Meintzschel F, Ziemann U.Modification of practice-dependent plasticity in human motor cortex by neuromodulators. Cereb Cortex2005:(in press).
76.
Bütefisch CM, Davis BC, Sawaki L, et al.Modulation of use-dependent plasticity by d-amphetamine. Ann Neurol2002;51(1):59-68.
77.
Sawaki L, Cohen LG, Classen J, Davis BC, Butefisch CM.Enhancement of use-dependent plasticity by D-amphetamine. Neurology2002;59(8):1262-1264.
78.
Sawaki L, Yaseen Z, Kopylev L, Cohen LG.Age-dependent changes in the ability to encode a novel elementary motor memory. Ann Neurol2003;53(4):521-524.
79.
Sawaki L, Werhahn KJ, Barco R, Kopylev L, Cohen LG.Effect of an alpha(1)-adrenergic blocker on plasticity elicited by motor training. Exp Brain Res2003;148(4):504-508.
80.
Sawaki L, Boroojerdi B, Kaelin-Lang A, et al.Cholinergic influences on use-dependent plasticity. J Neurophysiol2002;87(1):166-171.
81.
Tegenthoff M, Witscher K, Schwenkreis P, Liepert J.Pharmacological modulation of training-induced plastic changes in human motor cortex. Electroencephalogr Clin Neurophysiol Suppl1999;51:188-196.
82.
Schwenkreis P, Witscher K, Pleger B, Malin JP, Tegenthoff M.The NMDA antagonist memantine affects training induced motor cortex plasticity—a study using transcranial magnetic stimulation. BMC Neurosci2005;6(1):35.
83.
Tegenthoff M, Cornelius B, Pleger B, Malin JP, Schwenkreis P.Amphetamine enhances training-induced motor cortex plasticity. Acta Neurol Scand2004;109(5):330-336.
84.
Pleger B, Schwenkreis P, Grunberg C, Malin JP, Tegenthoff M.Fluoxetine facilitates use-dependent excitability of human primary motor cortex. Clin Neurophysiol2004;115(9):2157-2163.
85.
Fu QG, Flament D, Coltz JD, Ebner TJ.Temporal encoding of movement kinematics in the discharge of primate primary motor and premotor neurons. J Neurophysiol1995;73(2):836-854.
86.
Stefan K, Cohen LG, Duque J, et al.Formation of a motor memory by action observation. J Neurosci2005;25(41):9339-9346.
87.
Feeney DM, Sutton RL.Pharmacotherapy for recovery of function after brain injury. Crit Rev Neurobiol1987;3(2):135-197.
88.
Feeney DM.Mechanisms of noradrenergic modulation of physical therapy: effects on functional recovery after cortical injury. In: Goldstein LB, ed. Advances in pharmacotherapy for recovery after stroke. Armonk, NY: Futura; 1998:35-77.
89.
Martinsson L, Wahlgren NG, Hardemark HG.Amphetamines for improving recovery after stroke. Cochrane Database Syst Rev2003(3):CD002090.
90.
Crisostomo EA, Duncan PW, Propst M, Dawson DV, Davis JN.Evidence that amphetamine with physical therapy promotes recovery of motor function in stroke patients. Ann Neurol1988;23(1):94-97.
91.
Walker-Batson D, Smith P, Curtis S, Unwin H, Greenlee R.Amphetamine paired with physical therapy accelerates motor recovery after stroke. Further evidence. Stroke1995;26(12): 2254-2259.
92.
Martinsson L, Wahlgren NG.Safety of dexamphetamine in acute ischemic stroke: a randomized, double-blind, controlled dose-escalation trial. Stroke2003;34(2):475-481.
93.
Sonde L, Nordstrom M, Nilsson CG, Lokk J, Viitanen M.A double-blind placebo-controlled study of the effects of amphetamine and physiotherapy after stroke. Cerebrovasc Dis2001;12(3): 253-257.
94.
Treig T, Werner C, Sachse M, Hesse S.No benefit from D-amphetamine when added to physiotherapy after stroke: a randomized, placebo-controlled study. Clin Rehabil2003;17(6):590-599.
95.
Flöel A, Hummel F, Breitenstein C, Knecht S, Cohen LG.Dopaminergic effects on encoding of a motor memory in chronic stroke. Neurology2005;65(3):472-474.
96.
Pariente J, Loubinoux I, Carel C, et al.Fluoxetine modulates motor performance and cerebral activation of patients recovering from stroke. Ann Neurol2001;50(6):718-729.
97.
Dobkin BH.Rehabilitation and functional neuroimaging dose-response trajectories for clinical trials. Neurorehabil Neural Repair2005;19(4):276-282.
98.
Goldstein LB, Matchar DB, Morgenlander JC, Davis JN.Influence of drugs on the recovery of sensorimotor function after stroke. J Neurol Rehabil1990;4:137-144.
99.
Goldstein LB.Common drugs may influence motor recovery after stroke. The Sygen in Acute Stroke Study Investigators. Neurology1995;45(5):865-871.
100.
Muellbacher W, Richards C, Ziemann U, et al.Improving hand function in chronic stroke. Arch Neurol2002;59(8):1278-1282.
101.
Scheidtmann K, Fries W, Muller F, Koenig E.Effect of levodopa in comb ination with physiotherapy on functional motor recovery after stroke: a prospective, randomised, double-blind study. Lancet2001;358(9284):787-790.
102.
Grade C, Redford B, Chrostowski J, Toussaint L, Blackwell B.Methylphenidate in early poststroke recovery: a double-blind, placebo-controlled study. Arch Phys Med Rehabil1998;79:1047-1050.
103.
Berthier ML, Pujol J, Gironell A, et al.Beneficial effect of donepezil on sensorimotor function after stroke. Am J Phys Med Rehabil2003;82(9):725-729.
104.
Dam M, Tonin P, De Boni A, et al.Effects of fluoxetine and maprotiline on functional recovery in poststroke hemiplegic patients undergoing rehabilitation therapy. Stroke1996;27(7):1211-1214.
