Top

Published in:

01-03-2015 | Original Article

Motor cortex excitability and connectivity in chronic stroke: a multimodal model of functional reorganization

Authors: Lukas J. Volz, Anna-Sophia Sarfeld, Svenja Diekhoff, Anne K. Rehme, Eva-Maria Pool, Simon B. Eickhoff, Gereon R. Fink, Christian Grefkes

Published in: Brain Structure and Function | Issue 2/2015

Abstract

Cerebral ischemia triggers a cascade of cellular processes, which induce neuroprotection, inflammation, apoptosis and regeneration. At the neural network level, lesions concomitantly induce cerebral plasticity. Yet, many stroke survivors are left with a permanent motor deficit, and only little is known about the neurobiological factors that determine functional outcome after stroke. Transcranial magnetic stimulation (TMS) and magnetic resonance imaging (MRI) are non-invasive approaches that allow insights into the functional (re-) organization of the cortical motor system. We here combined neuronavigated TMS, MRI and analyses of connectivity to investigate to which degree recovery of hand function depends on corticospinal tract (CST) damage and biomarkers of cerebral plasticity like cortical excitability and motor network effective connectivity. As expected, individual motor performance of 12 stroke patients with persistent motor deficits was found to depend upon the degree of CST damage but also motor cortex excitability and interhemispheric connectivity. In addition, the data revealed a strong correlation between reduced ipsilesional motor cortex excitability and reduced interhemispheric inhibition in severely impaired patients. Interindividual differences in ipsilesional motor cortex excitability were stronger related to the motor deficit than abnormal interhemispheric connectivity or CST damage. Multivariate linear regression analysis combining the three factors accounted for more than 80 % of the variance in functional impairment. The inter-relation of cortical excitability and reduced interhemispheric inhibition provides direct multi-modal evidence for the disinhibition theory of the contralesional hemisphere following stroke. Finally, our data reveal a key mechanism (i.e., the excitability-related reduction in interhemispheric inhibition) accounting for the rehabilitative potential of novel therapeutic approaches which aim at modulating cortical excitability in stroke patients.

Available only for authorised users

Adeyemo BO, Simis M, Macea DD, Fregni F (2012) Systematic review of parameters of stimulation, clinical trial design characteristics, and motor outcomes in non-invasive brain stimulation in stroke. Front Psychiatry 3:88CrossRefPubMedCentralPubMed

Ameli M, Grefkes C, Kemper F, Riegg FP, Rehme AK, Karbe H, Fink GR, Nowak DA (2009) Differential effects of high-frequency repetitive transcranial magnetic stimulation over ipsilesional primary motor cortex in cortical and subcortical middle cerebral artery stroke. Ann Neurol 66(3):298–309CrossRefPubMed

Ashburner J, Friston KJ (2005) Unified segmentation. Neuroimage 26(3):839–851CrossRefPubMed

Benjamini Y, Hochberg Y (1995) Controlling the false discovery rate: a practical and powerfull approach to multiple testing. J R Stat Soc Ser B (Methodological) 57(1):289–300

Boroojerdi B, Diefenbach K, Ferbert A (1996) Transcallosal inhibition in cortical and subcortical cerebral vascular lesions. J Neurol Sci 144(1–2):160–170CrossRefPubMed

Boudrias MH, Goncalves CS, Penny WD, Park CH, Rossiter HE, Talelli P, Ward NS (2012) Age-related changes in causal interactions between cortical motor regions during hand grip. Neuroimage 59(4):3398–3405CrossRefPubMedCentralPubMed

Brott T, Adams HP Jr, Olinger CP, Marler JR, Barsan WG, Biller J, Spilker J, Holleran R, Eberle R, Hertzberg V et al (1989) Measurements of acute cerebral infarction: a clinical examination scale. Stroke 20(7):864–870CrossRefPubMed

Burgel U, Schormann T, Schleicher A, Zilles K (1999) Mapping of histologically identified long fiber tracts in human cerebral hemispheres to the MRI volume of a reference brain: position and spatial variability of the optic radiation. Neuroimage 10(5):489–499CrossRefPubMed

Byrnes ML, Thickbroom GW, Phillips BA, Wilson SA, Mastaglia FL (1999) Physiological studies of the corticomotor projection to the hand after subcortical stroke. Clin Neurophysiol 110(3):487–498CrossRefPubMed

Byrnes ML, Thickbroom GW, Phillips BA, Mastaglia FL (2001) Long-term changes in motor cortical organisation after recovery from subcortical stroke. Brain Res 889(1–2):278–287CrossRefPubMed

Calautti C, Leroy F, Guincestre JY, Marie RM, Baron JC (2001) Sequential activation brain mapping after subcortical stroke: changes in hemispheric balance and recovery. NeuroReport 12(18):3883–3886CrossRefPubMed

Cardenas-Morales L, Volz LJ, Michely J, Rehme AK, Pool EM, Nettekoven C, Eickhoff SB, Fink GR, Grefkes C (2013) Network connectivity and individual responses to brain stimulation in the human motor system. Cereb Cortex. doi:10.1093/cercor/bht023 PubMed

Catano A, Houa M, Caroyer JM, Ducarne H, Noel P (1996) Magnetic transcranial stimulation in acute stroke: early excitation threshold and functional prognosis. EEG Clin Neurophysiol 101(3):233–239

Cheeran B, Talelli P, Mori F, Koch G, Suppa A, Edwards M, Houlden H, Bhatia K, Greenwood R, Rothwell JC (2008) A common polymorphism in the brain-derived neurotrophic factor gene (BDNF) modulates human cortical plasticity and the response to rTMS. J Physiol 586(23):5717–5725CrossRefPubMedCentralPubMed

Cicinelli P, Traversa R, Bassi A, Scivoletto G, Rossini PM (1997) Interhemispheric differences of hand muscle representation in human motor cortex. Muscle Nerve 20(5):535–542CrossRefPubMed

Cicinelli P, Pasqualetti P, Zaccagnini M, Traversa R, Oliveri M, Rossini PM (2003) Interhemispheric asymmetries of motor cortex excitability in the postacute stroke stage: a paired-pulse transcranial magnetic stimulation study. Stroke 34(11):2653–2658CrossRefPubMed

Classen J, Schnitzler A, Binkofski F, Werhahn KJ, Kim YS, Kessler KR, Benecke R (1997) The motor syndrome associated with exaggerated inhibition within the primary motor cortex of patients with hemiparetic. Brain 120(4):605–619CrossRefPubMed

Dancause N, Nudo RJ (2011) Shaping plasticity to enhance recovery after injury. Prog Brain Res 192:273–295CrossRefPubMedCentralPubMed

Day BL, Dressler D, de Maertens Noordhout A, Marsden CD, Nakashima K, Rothwell JC, Thompson PD (1989) Electric and magnetic stimulation of human motor cortex: surface EMG and single motor unit responses. J Physiol 412:449–473CrossRefPubMedCentralPubMed

Devanne H, Lavoie BA, Capaday C (1997) Input-output properties and gain changes in the human corticospinal pathway. Exp Brain Res 114(2):329–338CrossRefPubMed

Di Lazzaro V, Restuccia D, Oliviero A, Profice P, Ferrara L, Insola A, Mazzone P, Tonali P, Rothwell JC (1998) Effects of voluntary contraction on descending volleys evoked by transcranial stimulation in conscious humans. J Physiol 508(2):625–633CrossRefPubMedCentralPubMed

Dum RP, Strick PL (1991) The origin of corticospinal projections from the premotor areas in the frontal lobe. J Neurosci 11(3):667–689PubMed

Eickhoff SB, Grefkes C (2011) Approaches for the integrated analysis of structure, function and connectivity of the human brain. Clin EEG Neurosci 42(2):107–121CrossRefPubMed

Eickhoff SB, Stephan KE, Mohlberg H, Grefkes C, Fink GR, Amunts K, Zilles K (2005) A new SPM toolbox for combining probabilistic cytoarchitectonic maps and functional imaging data. Neuroimage 25(4):1325–1335CrossRefPubMed

Escudero JV, Sancho J, Bautista D, Escudero M, Lopez-Trigo J (1998) Prognostic value of motor evoked potential obtained by transcranial magnetic brain stimulation in motor function recovery in patients with acute ischemic stroke. Stroke 29(9):1854–1859CrossRefPubMed

Ferbert A, Priori A, Rothwell JC, Day BL, Colebatch JG, Marsden CD (1992) Interhemispheric inhibition of the human motor cortex. J Physiol 453:525–546CrossRefPubMedCentralPubMed

Friston KJ, Harrison L, Penny W (2003) Dynamic causal modelling. Neuroimage 19(4):1273–1302CrossRefPubMed

Gerloff C, Bushara K, Sailer A, Wassermann EM, Chen R, Matsuoka T, Waldvogel D, Wittenberg GF, Ishii K, Cohen LG, Hallett M (2006) Multimodal imaging of brain reorganization in motor areas of the contralesional hemisphere of well recovered patients after capsular stroke. Brain 129(3):791–808CrossRefPubMed

Grefkes C, Fink GR (2011) Reorganization of cerebral networks after stroke: new insights from neuroimaging with connectivity approaches. Brain 134(5):1264–1276CrossRefPubMedCentralPubMed

Grefkes C, Fink GR (2012) Disruption of motor network connectivity post-stroke and its noninvasive neuromodulation. Curr Opin Neurol 25(6):670–675CrossRefPubMed

Grefkes C, Nowak DA, Eickhoff SB, Dafotakis M, Kust J, Karbe H, Fink GR (2008) Cortical connectivity after subcortical stroke assessed with functional magnetic resonance imaging. Ann Neurol 63(2):236–246CrossRefPubMed

Hamada M, Murase N, Hasan A, Balaratnam M, Rothwell JC (2013) The role of interneuron networks in driving human motor cortical plasticity. Cereb Cortex 23(7):1593–1605CrossRefPubMed

Hummel FC, Cohen LG (2006) Non-invasive brain stimulation: a new strategy to improve neurorehabilitation after stroke? Lancet Neurol 5(8):708–712CrossRefPubMed

Kandel M, Beis JM, Le Chapelain L, Guesdon H, Paysant J (2012) Non-invasive cerebral stimulation for the upper limb rehabilitation after stroke: a review. Ann Phys Rehabil Med 55(9–10):657–680CrossRefPubMed

Kim YH, You SH, Ko MH, Park JW, Lee KH, Jang SH, Yoo WK, Hallett M (2006) Repetitive transcranial magnetic stimulation-induced corticomotor excitability and associated motor skill acquisition in chronic stroke. Stroke 37(6):1471–1476CrossRefPubMed

Liepert J (2005) Transcranial magnetic stimulation in neurorehabilitation. Acta Neurochir Suppl 93:71–74CrossRefPubMed

Liepert J, Restemeyer C, Kucinski T, Zittel S, Weiller C (2005) Motor strokes: the lesion location determines motor excitability changes. Stroke 36(12):2648–2653CrossRefPubMed

Lyle RC (1981) A performance test for assessment of upper limb function in physical rehabilitation treatment and research. Int J Rehabil Res 4:483–492CrossRefPubMed

Macdonell RA, Donnan GA, Bladin PF (1989) A comparison of somatosensory evoked and motor evoked potentials in stroke. Ann Neurol 25(1):68–73CrossRefPubMed

Murase N, Duque J, Mazzocchio R, Cohen LG (2004) Influence of interhemispheric interactions on motor function in chronic stroke. Ann Neurol 55(3):400–409CrossRefPubMed

Nardone R, Tezzon F (2002) Inhibitory and excitatory circuits of cerebral cortex after ischaemic stroke: prognostic value of the transcranial magnetic stimulation. EMG Clin Neurophysiol 42(3):131–136

Nelson AJ, Hoque T, Gunraj C, Ni Z, Chen R (2009) Bi-directional interhemispheric inhibition during unimanual sustained contractions. BMC Neurosci 10:31CrossRefPubMedCentralPubMed

Newton JM, Ward NS, Parker GJ, Deichmann R, Alexander DC, Friston KJ, Frackowiak RS (2006) Non-invasive mapping of corticofugal fibres from multiple motor areas—relevance to stroke recovery. Brain 129(7):1844–1858CrossRefPubMedCentralPubMed

Ngomo S, Leonard G, Moffet H, Mercier C (2012) Comparison of transcranial magnetic stimulation measures obtained at rest and under active conditions and their reliability. J Neurosci Methods 205(1):65–71CrossRefPubMed

Nowak DA, Grefkes C, Ameli M, Fink GR (2009) Interhemispheric competition after stroke: brain stimulation to enhance recovery of function of the affected hand. Neurorehabil Neural Repair 23(7):641–656CrossRefPubMed

Paulus W, Classen J, Cohen LG, Large CH, Di Lazzaro V, Nitsche M, Pascual-Leone A, Rosenow F, Rothwell JC, Ziemann U (2008) State of the art: pharmacologic effects on cortical excitability measures tested by transcranial magnetic stimulation. Brain Stimul 1(3):151–163CrossRefPubMed

Pekna M, Pekny M, Nilsson M (2012) Modulation of neural plasticity as a basis for stroke rehabilitation. Stroke 43(10):2819–2828CrossRefPubMed

Penny WD, Stephan KE, Mechelli A, Friston KJ (2004) Comparing dynamic causal models. Neuroimage 22(3):1157–1172CrossRefPubMed

Pool EM, Rehme AK, Fink GR, Eickhoff SB, Grefkes C (2013) Network dynamics engaged in the modulation of motor behavior in healthy subjects. Neuroimage 82:68–76CrossRefPubMed

Radlinska BA, Blunk Y, Leppert IR, Minuk J, Pike GB, Thiel A (2012) Changes in callosal motor fiber integrity after subcortical stroke of the pyramidal tract. J Cereb Blood Flow Metab 32(8):1515–1524CrossRefPubMedCentralPubMed

Rehme AK, Eickhoff SB, Wang LE, Fink GR, Grefkes C (2011) Dynamic causal modeling of cortical activity from the acute to the chronic stage after stroke. Neuroimage 55(3):1147–1158CrossRefPubMed

Rehme AK, Eickhoff SB, Rottschy C, Fink GR, Grefkes C (2012) Activation likelihood estimation meta-analysis of motor-related neural activity after stroke. Neuroimage 59(3):2771–2782CrossRefPubMed

Rothwell JC, Hallett M, Berardelli A, Eisen A, Rossini P, Paulus W (1999) Magnetic stimulation: motor evoked potentials. The International Federation of Clinical Neurophysiology. EEG Clin Neurophysiol Suppl 52:97–103

Sarfeld AS, Diekhoff S, Wang LE, Liuzzi G, Uludag K, Eickhoff SB, Fink GR, Grefkes C (2012) Convergence of human brain mapping tools: neuronavigated TMS parameters and fMRI activity in the hand motor area. Hum Brain Mapp 33(5):1107–1123CrossRefPubMed

Schulz R, Park CH, Boudrias MH, Gerloff C, Hummel FC, Ward NS (2012) Assessing the integrity of corticospinal pathways from primary and secondary cortical motor areas after stroke. Stroke 43(8):2248–2251CrossRefPubMedCentralPubMed

Shimizu T, Hosaki A, Hino T, Sato M, Komori T, Hirai S, Rossini PM (2002) Motor cortical disinhibition in the unaffected hemisphere after unilateral cortical stroke. Brain 125(8):1896–1907CrossRefPubMed

Stephan KE, Penny WD, Daunizeau J, Moran RJ, Friston KJ (2009) Bayesian model selection for group studies. Neuroimage 46(4):1004–1017CrossRefPubMedCentralPubMed

Stinear CM, Barber PA, Smale PR, Coxon JP, Fleming MK, Byblow WD (2007) Functional potential in chronic stroke patients depends on corticospinal tract integrity. Brain 130(1):170–180CrossRefPubMed

Stinear CM, Barber PA, Petoe M, Anwar S, Byblow WD (2012) The PREP algorithm predicts potential for upper limb recovery after stroke. Brain 135(8):2527–2535CrossRefPubMed

Talelli P, Greenwood RJ, Rothwell JC (2006) Arm function after stroke: neurophysiological correlates and recovery mechanisms assessed by transcranial magnetic stimulation. Clin Neurophysiol 117(8):1641–1659CrossRefPubMed

Thickbroom GW, Byrnes ML, Archer SA, Mastaglia FL (2002) Motor outcome after subcortical stroke: MEPs correlate with hand strength but not dexterity. Clin Neurophysiol 113(12):2025–2029CrossRefPubMed

Traversa R, Cicinelli P, Pasqualetti P, Filippi M, Rossini PM (1998) Follow-up of interhemispheric differences of motor evoked potentials from the ‘affected’ and ‘unaffected’ hemispheres in human stroke. Brain Res 803(1–2):1–8CrossRefPubMed

Turton A, Wroe S, Trepte N, Fraser C, Lemon RN (1996) Contralateral and ipsilateral EMG responses to transcranial magnetic stimulation during recovery of arm and hand function after stroke. EEG Clin Neurophysiol 101(4):316–328

van Swieten JC, Koudstaal PJ, Visser MC, Schouten HJ, van Gijn J (1988) Interobserver agreement for the assessment of handicap in stroke patients. Stroke 19(5):604–607CrossRefPubMed

Veerbeek JM, Kwakkel G, van Wegen EE, Ket JC, Heymans MW (2011) Early prediction of outcome of activities of daily living after stroke: a systematic review. Stroke 42(5):1482–1488CrossRefPubMed

von Giesen HJ, Roick H, Benecke R (1994) Inhibitory actions of motor cortex following unilateral brain lesions as studied by magnetic brain stimulation. Exp Brain Res 99(1):84–96CrossRef

Wang LE, Fink GR, Diekhoff S, Rehme AK, Eickhoff SB, Grefkes C (2011) Noradrenergic enhancement improves motor network connectivity in stroke patients. Ann Neurol 69(2):375–388CrossRefPubMed

Wang LE, Tittgemeyer M, Imperati D, Diekhoff S, Ameli M, Fink GR, Grefkes C (2012) Degeneration of corpus callosum and recovery of motor function after stroke: a multimodal magnetic resonance imaging study. Hum Brain Mapp 33(12):2941–2956CrossRefPubMed

Ward NS, Brown MM, Thompson AJ, Frackowiak RS (2003) Neural correlates of motor recovery after stroke: a longitudinal fMRI study. Brain 126(11):2476–2496CrossRefPubMedCentralPubMed

Ward NS, Newton JM, Swayne OB, Lee L, Thompson AJ, Greenwood RJ, Rothwell JC, Frackowiak RS (2006) Motor system activation after subcortical stroke depends on corticospinal system integrity. Brain 129(3):809–819CrossRefPubMedCentralPubMed

Weiss C, Nettekoven C, Rehme AK, Neuschmelting V, Eisenbeis A, Goldbrunner R, Grefkes C (2012) Mapping the hand, foot and face representations in the primary motor cortex—retest reliability of neuronavigated TMS versus functional MRI. Neuroimage 66C:531–542

Yousry TA, Schmid UD, Alkadhi H, Schmidt D, Peraud A, Buettner A, Winkler P (1997) Localization of the motor hand area to a knob on the precentral gyrus. A new landmark. Brain 120(1):141–157CrossRefPubMed

Yozbatiran N, Der-Yeghiaian L, Cramer SC (2008) A standardized approach to performing the action research arm test. Neurorehabil Neural Repair 22(1):78–90CrossRefPubMed

Ziemann U (2011) Transcranial magnetic stimulation at the interface with other techniques: a powerful tool for studying the human cortex. Neuroscientist 17(4):368–381CrossRefPubMed

Ziemann U, Lonnecker S, Steinhoff BJ, Paulus W (1996) Effects of antiepileptic drugs on motor cortex excitability in humans: a transcranial magnetic stimulation study. Ann Neurol 40(3):367–378CrossRefPubMed

Title: Motor cortex excitability and connectivity in chronic stroke: a multimodal model of functional reorganization
Authors: Lukas J. Volz
Anna-Sophia Sarfeld
Svenja Diekhoff
Anne K. Rehme
Eva-Maria Pool
Simon B. Eickhoff
Gereon R. Fink
Christian Grefkes
Publication date: 01-03-2015
Publisher: Springer Berlin Heidelberg
Published in: Brain Structure and Function / Issue 2/2015
Print ISSN: 1863-2653
Electronic ISSN: 1863-2661
DOI: https://doi.org/10.1007/s00429-013-0702-8

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Motor cortex excitability and connectivity in chronic stroke: a multimodal model of functional reorganization

Abstract

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 2/2015

Differential impact of chronic stress along the hippocampal dorsal–ventral axis

Integrity of cortical perineuronal nets influences corticospinal tract plasticity after spinal cord injury

The role of the right temporoparietal junction in attention and social interaction as revealed by ALE meta-analysis

Age-related decrease of functional connectivity additional to gray matter atrophy in a network for movement initiation

Insular and caudate lesions release abnormal yawning in stroke patients

Orienting movements in area 9 identified by long-train ICMS