Abstract
Several paired-associative stimulation (PAS) protocols induce neuroplastic changes in human motor cortex (M1). To understand better the inherent variability of responses to PAS, we investigated the effectiveness and reproducibility of two PAS paradigms, and neurophysiological and experimental variables that may influence this. Motor evoked potentials (MEPs) were elicited by transcranial magnetic stimulation (TMS) of right M1, and recorded from surface EMG of left abductor pollicis brevis (APB) and first dorsal interosseous before and after PAS. PAS consisted of electrical stimulation of left median nerve paired with TMS over right M1 25 ms later. Twenty subjects were given one of two PAS protocols: short (132 paired stimuli at 0.2 Hz) or long (90 paired stimuli at 0.05 Hz), and were re-tested with the same protocol on 3 separate occasions, with 11 subjects tested in the morning and 9 in the afternoon. Neurophysiological variables assessed included MEP amplitude, resting and active motor threshold, short-interval intracortical inhibition, intracortical facilitation and cortical silent period duration. The short PAS protocol produced greater APB MEP facilitation (51%) than the long protocol (11%), and this did not differ between sessions. The neurophysiological variables did not consistently predict responses to PAS. Both PAS protocols induced more APB MEP facilitation, and greater reproducibility between sessions, in experiments conducted in the afternoon. The mechanism for this is unclear, but circadian rhythms in hormones and neuromodulators known to influence neuroplasticity warrant investigation. Future studies involving PAS should be conducted at a fixed time of day, preferably in the afternoon, to maximise neuroplasticity and reduce variability.
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Brasil-Neto JP, McShane LM, Fuhr P, Hallett M, Cohen LG (1992) Topographic mapping of the human motor cortex with magnetic stimulation: factors affecting accuracy and reproducibility. Electroencephalogr Clin Neurophysiol 85:9–16
Burke D, Hicks R, Stephen J, Woodforth I, Crawford M (1995) Trial-to-trial variability of corticospinal volleys in human subjects. Electroencephalogr Clin Neurophysiol 97:231–237
Chaudhury D, Wang LM, Colwell CS (2005) Circadian regulation of hippocampal long-term potentiation. J Biol Rhythms 20:225–236
Collins DR, Davies SN (1997) Melatonin blocks the induction of long-term potentiation in an N-methyl-D-aspartate independent manner. Brain Res 767:162–165
de Quervain DJ, Roozendaal B, Nitsch RM, McGaugh JL, Hock C (2000) Acute cortisone administration impairs retrieval of long-term declarative memory in humans. Nat Neurosci 3:313–314
Dubrovsky B, Williams D, Kraulis I (1985) Effects of corticosterone and 5 alpha-dihydrocorticosterone on brain excitability in the rat. J Neurosci Res 14:117–128
Ellaway PH, Davey NJ, Maskill DW, Rawlinson SR, Lewis HS, Anissimova NP (1998) Variability in the amplitude of skeletal muscle responses to magnetic stimulation of the motor cortex in man. Electroencephalogr Clin Neurophysiol 109:104–113
El-Sherif Y, Tesoriero J, Hogan MV, Wieraszko A (2003) Melatonin regulates neuronal plasticity in the hippocampus. J Neurosci Res 72:454–460
Fratello F, Veniero D, Curcio G, Ferrara M, Marzano C, Moroni F, Pellicciari MC, Bertini M, Rossini PM, De Gennaro L (2006) Modulation of corticospinal excitability by paired associative stimulation: reproducibility of effects and intraindividual reliability. Clin Neurophysiol 117:2667–2674
Funase K, Miles TS, Gooden BR (1999) Trial-to-trial fluctuations in H-reflexes and motor evoked potentials in human wrist flexor. Neurosci Lett 271:25–28
Ilic TV, Meintzschel F, Cleff U, Ruge D, Kessler KR, Ziemann U (2002) Short-interval paired-pulse inhibition and facilitation of human motor cortex: the dimension of stimulus intensity. J Physiol 545:153–167
Ilic TV, Jung P, Ziemann U (2004) Subtle hemispheric asymmetry of motor cortical inhibitory tone. Clin Neurophysiol 115:330–340
Koski L, Schrader LM, Wu AD, Stern JM (2005) Normative data on changes in transcranial magnetic stimulation measures over a ten hour period. Clin Neurophysiol 116:2099–2109
Kujirai T, Caramia MD, Rothwell JC, Day BL, Thompson PD, Ferbert A, Wroe S, Asselman P, Marsden CD (1993) Corticocortical inhibition in human motor cortex. J Physiol 471:501–519
Kujirai K, Kujirai T, Sinkjaer T, Rothwell JC (2006) Associative plasticity in human motor cortex under voluntary muscle contraction. J Neurophysiol 96:1337–1346
Liepert J, Schwenkreis P, Tegenthoff M, Malin JP (1997) The glutamate antagonist riluzole suppresses intracortical facilitation. J Neural Transm 104:1207–1214
McIntyre IM, Norman TR, Burrows GD, Armstrong SM (1987) Melatonin rhythm in human plasma and saliva. J Pineal Res 4:177–183
Morgante F, Espay AJ, Gunraj C, Lang AE, Chen R (2006) Motor cortex plasticity in Parkinson’s disease and levodopa-induced dyskinesias. Brain 129:1059–1069
Newcomer JW, Selke G, Melson AK, Hershey T, Craft S, Richards K, Alderson AL (1999) Decreased memory performance in healthy humans induced by stress-level cortisol treatment. Arch Gen Psychiatry 56:527–533
Nudo RJ, Wise BM, SiFuentes F, Milliken GW (1996) Neural substrates for the effects of rehabilitative training on motor recovery after ischemic infarct. Science 272:1791–1794
Oldfield RC (1971) The assessment and analysis of handedness: the Edinburgh inventory. Neuropsychologia 9:97–113
Pascual-Leone A, Valls-Sole J, Wassermann EM, Hallett M (1994) Responses to rapid-rate transcranial magnetic stimulation of the human motor cortex. Brain 117(Pt 4):847–858
Quartarone A, Bagnato S, Rizzo V, Siebner HR, Dattola V, Scalfari A, Morgante F, Battaglia F, Romano M, Girlanda P (2003) Abnormal associative plasticity of the human motor cortex in writer’s cramp. Brain 126:2586–2596
Raghavan AV, Horowitz JM, Fuller CA (1999) Diurnal modulation of long-term potentiation in the hamster hippocampal slice. Brain Res 833:311–314
Ranjit N, Young EA, Raghunathan TE, Kaplan GA (2005) Modeling cortisol rhythms in a population-based study. Psychoneuroendocrinology 30:615–624
Ridding MC, Flavel SC (2006) Induction of plasticity in the dominant and non-dominant motor cortices of humans. Exp Brain Res 171:551–557
Ridding MC, Taylor JL (2001) Mechanisms of motor-evoked potential facilitation following prolonged dual peripheral and central stimulation in humans. J Physiol 537:623–631
Ridding MC, McKay DR, Thompson PD, Miles TS (2001) Changes in corticomotor representations induced by prolonged peripheral nerve stimulation in humans. Clin Neurophysiol 112:1461–1469
Rossini PM, Desiato MT, Lavaroni F, Caramia MD (1991) Brain excitability and electroencephalographic activation: non-invasive evaluation in healthy humans via transcranial magnetic stimulation. Brain Res 567:111–119
Sale MV, Ridding MC, Nordstrom MA (2006) Variability of two paired associative stimulation (PAS) protocols used to induce neuroplastic changes in human motor cortex. Proc Australasian Wint Conf Brain Res 24:10.5
Sanes JN, Donoghue JP (2000) Plasticity and primary motor cortex. Annu Rev Neurosci 23:393–415
Shrout PE, Fleiss JL (1979) Intraclass Correlations: Uses in Assessing Rater Reliability. Psychol Bull 2:420–428
Smith MJ, Keel JC, Greenberg BD, Adams LF, Schmidt PJ, Rubinow DA, Wassermann EM (1999) Menstrual cycle effects on cortical excitability. Neurology 53:2069
Stefan K, Kunesch E, Cohen LG, Benecke R, Classen J (2000) Induction of plasticity in the human motor cortex by paired associative stimulation. Brain 123(Pt 3):572–584
Stefan K, Kunesch E, Benecke R, Cohen LG, Classen J (2002) Mechanisms of enhancement of human motor cortex excitability induced by interventional paired associative stimulation. J Physiol 543:699–708
Stefan K, Wycislo M, Classen J (2004) Modulation of associative human motor cortical plasticity by attention. J Neurophysiol 92:66–72
Stefan K, Wycislo M, Gentner R, Schramm A, Naumann M, Reiners K, Classen J (2006) Temporary occlusion of associative motor cortical plasticity by prior dynamic motor training. Cereb Cortex 16:376–385
Touge T, Gerschlager W, Brown P, Rothwell JC (2001) Are the after-effects of low-frequency rTMS on motor cortex excitability due to changes in the efficacy of cortical synapses? Clin Neurophysiol 112:2138–2145
Uy J, Ridding MC, Hillier S, Thompson PD, Miles TS (2003) Does induction of plastic change in motor cortex improve leg function after stroke? Neurology 61:982–984
Werhahn KJ, Kunesch E, Noachtar S, Benecke R, Classen J (1999) Differential effects on motorcortical inhibition induced by blockade of GABA uptake in humans. J Physiol 517(Pt 2):591–597
Wolters A, Sandbrink F, Schlottmann A, Kunesch E, Stefan K, Cohen LG, Benecke R, Classen J (2003) A temporally asymmetric Hebbian rule governing plasticity in the human motor cortex. J Neurophysiol 89:2339–2345
Ziemann U, Ilic TV, Pauli C, Meintzschel F, Ruge D (2004) Learning modifies subsequent induction of long-term potentiation-like and long-term depression-like plasticity in human motor cortex. J Neurosci 24:1666–1672
Acknowledgments
This work was funded by a grant (no. 349452) from the NH&MRC of Australia, and the Physiotherapy Research Foundation of Australia. It forms a component of the PhD studies of MVS, who is supported by a NH&MRC Dora Lush Biomedical Research scholarship. MCR holds a Queen Elizabeth II Fellowship from the Australian Research Council. The authors would like to thank Dr. Julian Taylor for his assistance with statistical analysis.
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Sale, M.V., Ridding, M.C. & Nordstrom, M.A. Factors influencing the magnitude and reproducibility of corticomotor excitability changes induced by paired associative stimulation. Exp Brain Res 181, 615–626 (2007). https://doi.org/10.1007/s00221-007-0960-x
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DOI: https://doi.org/10.1007/s00221-007-0960-x