the motor system is a dynamic network of cortical and subcortical areas interacting through excitatory and inhibitory circuits , modulated by somatosensory input . modifications of cortical excitability enable recovery and reorganization of the remaining motor areas both in animal models [ 4 , 5 ] and in humans [ 1 , 6 ] . transcranial magnetic stimulation ( tms ) and magnetoencephalography ( meg ) have both been applied in stroke patients to reveal cortical excitability changes . motor threshold ( mt ) , that is , the minimal tms intensity eliciting motor evoked potentials ( meps ) , is related to membrane excitability as it is influenced by drugs affecting neuronal ion channels . paired pulse tms ( pp - tms ) reveals short - interval intracortical inhibition ( sici ) , related to the activation of gaba - a receptors and intracortical facilitation ( icf ) attributed mainly to glutamatergic nmda receptor activation ( for references , see ) . in acute stroke , the mt is increased in the lesioned hemisphere ( lh ) whereas in the nonlesioned ( nh ) hemisphere it is normal   or decreased one month after stroke . sici is decreased in both hemispheres early after stroke ; icf is stronger in nh in severe than mild strokes [ 1 , 6 ] . finger movements and median nerve   or finger stimulation   modify spontaneous meg oscillations over the sensorimotor cortex in the beta band ( 1525  hz ) . they are suppressed at 100300  ms after tactile stimulation ( event - related desynchronization ; erd ) , reflecting increased excitability , and increased at 5001000  ms ( event - related synchronization ; ers ) , reflecting removal of excitation [ 12 , 13 ] or reduced excitability . inhibitory gaba - a agonist diazepam increases meg beta activity [ 15 , 16 ] . combined meg and magnetic resonance spectroscopy showed a linear relationship between the beta ers strength and gaba concentration . beta ers has been shown to be significantly weaker in the lh than nh ; stronger ers amplitude was correlated with a better affected hand function up to 3 months after stroke . reduction of beta ers , however , correlated with clinical improvement after physiotherapy of patients with chronic stroke . movement - related beta erd was significantly reduced in lh of stroke patients . the hand representation in the somatosensory cortex ( s1 ) , estimated by somatosensory evoked fields ( sefs ) , is the largest one month after stroke and its increase was correlated with the affected hand function . in tms mapping , hand motor representation expands in the lh up to 1 month . in animal models , somatosensory reorganization is activated immediately after the lesion by diminished gaba - a - related inhibition and by glutamatergic activation after one month . we hypothesized to see correlations between erd and mt related to the early cortical excitability and between ers and sici , both attributed to gaba - a - related processes . moreover , we expected that icf , reflecting glutamatergic activity , would correlate with the somatosensory modifications in meg , as glutamate is associated with late somatosensory plasticity . meg and ntms were recorded from thirteen patients ( age 67.3  11 years , 8 women ) , with first - ever ischemic stroke in the middle cerebral artery territory one ( t1 ) and three months after stroke ( t2 ) . six patients had a subcortical and seven patients had a subcorticocortical or cortical stroke ( table 1 ) . at t1 , one patient used amitriptyline 10  mg / day and another used citalopram 10  mg / day . one patient used zopiclone 7.5  mg for occasional sleeplessness . at t2 , citalopram 10  mg / day was used by one patient . data from these patients has been presented previously [ 18 , 21 , 23 , 24 ] . as the patients having both tms and meg recordings are a subset of the previous patient groups , we recalculated the group - level electrophysiological parameters to show that the present patient group is sufficiently similar to those reported previously ( see supplementary tables 1 and 2 in supplementary material available online at http://dx.doi.org/10.1155/2015/309546 ) . an eximia navigated magnetic stimulator with a coplanar figure - of - eight coil of 70  mm wing radius ( nexstim ltd . , helsinki , finland ) was used for ntms . patients ' mris , required for navigation , were scanned at t1 and used also at t2 . the site was then stimulated by single tms pulses at 110% of mt and by the pp - tms at 90% for conditioning and 110% of mt for test pulses . fifteen single pulses or pairs of conditioning and test pulses were delivered in each stimulation session . the interval between stimuli was 3.3  s and the intersession interval varied between 1 and 3  min . the isi selected for the paired - pulse stimuli was 2  ms for sici and 12  ms for icf . the peak - to - peak amplitudes of meps elicited by pp - tms were normalized by dividing them by the corresponding single - pulse mep amplitude to simplify subject - to - subject comparisons . meg during rest and tactile stimulation of the thumb ( d1 ) , index ( d2 ) , and little finger ( d5 ) were recorded with a 306-sensor neuromagnetometer ( elekta neuromag , helsinki , finland ) in biomag laboratory , right before the ntms measurement . time - frequency representations ( tfr ) in the 1030  hz band were calculated to define the frequency range of beta modulation , which was quantified by the temporal spectral evolution method ( tse ) from signals of 2 to 4 meg sensors showing the strongest reactivity . only the contralateral beta modifications ( the affected hand stimulation for the lh and the unaffected hand for nh ) were analyzed . onset and offset of the erd and ers were defined as a time point when the signal differed 2 sds from the baseline . the absolute erd and ers strengths were calculated from the peak amplitudes and converted into relative values in relation to the 300  ms prestimulus baseline . for sefs , about 120 responses were averaged for stimulation of d2 ( isi 3005  ms ) , and d1 and d5 ( isi 1005  ms ) in separate sessions . the size of the hand representation in the si was determined by calculating the euclidean distance in xyz - space between the equivalent current dipoles ( ecds ) of the earliest responses to d1 and d5 stimulation . multiple comparison correction was carried out according to the number of tests ( n = 32 ) suggested by the four prior hypotheses ( t1 and t2 were tested separately ; lh and nh variations lead to four tests in each case ; n = 442 = 32 ) . we also present significances of correlation values without multiple comparisons and supply all correlation coefficients and corresponding p values ( cf . [ 1 , 9 , 28 ] for a similar approach and   for its statistical aspects ) . the differences between ntms and meg values obtained at t1 and t2 were tested with student 's t - test . in the lh , meps were found in 11 patients both at t1 and at t2 and were present in the nh in all patients . mt was higher for lh than nh in 9 patients at t1 ( p < 0.05 , binomial test ) and in 10 patients at t2 ( p < 0.05 , binomial test ) . the mts in the lh and nh correlated strongly both at t1 ( r = .82 , p < .01 ) and at t2 ( r = .78 , p < .01 ) . pp2ms stimulations of nh did not inhibit meps ( disinhibition ; diminished sici ) in 5 patients at t1 and in 3 patients at t2 . pp12ms stimulation of lh facilitated meps ( icf ) in 10 out of 11 patients at t1 and in all patients at t2 . in nh mep amplitudes elicited by pp12ms stimulations were correlated between the lh and nh at t1 ( r = .62 ; p < .05 ) but not at t2 ( supplementary table 2 ) . erd started 140  10  ms after tactile stimulation and peaked at 250  10  ms . the subsequent ers started at 520  40  ms and peaked at 900  70  ms . at t1 , erd was absent in one patient and ers in two patients in the lh ; ers was missing from the nh in one patient . at t2 , ers was smaller in the lh than nh at t1 ( 46  31% versus 63  32% ; p < .05 ) ; at t2 , the difference was nonsignificant . sefs from both hemispheres were detected in 12 patients at t1 and in all patients at t2 . they were smaller in the lh than nh at t1 ( 25 nam versus 32 nam ; p < .04 ) but not at t2 . the si hand representation area was larger in the lh than nh at t1 ( 12  3  mm versus 10  3  mm p < .003 ) but not at t2 ( supplementary table 3 ) . the plots of the most relevant correlations are depicted in figure 1 to show that they were not driven by outliers . all correlations are displayed in table 2 to enable evaluation of significance of our hypotheses against general effects of the lesions . the mt and erd were correlated in the lh at t1 ( r = .66 , p < .03 ) , indicating that small erd was associated with a high mt ( figure 1(a ) ) . at t2 , this correlation was weaker ( r = .58 , p < .06 ) . however , the mt of the lh correlated with the erd of nh ( r = .62 , p < .04 ) , and the mt of the nh correlated with erd of the lh ( r = .65 , p < .02 ) , suggesting that high mt was associated with a small erd in the opposite hemisphere at t2 ( table 2 ) . sici and the ers did not correlate at t1 or in lh at t2 . in the nh , high ers was associated with a strong sici ( r = .59 , p < .04 ; figure 1(b ) ) . in addition to hypothesized correlations , sici of the nh and erd of the lh at t2 were correlated ( r = .82 , p < .001 ) , indicating that strong erd in the lh was associated with a strong sici in the nh . sici in the lh was correlated also with the si amplitude of the lh ( r = .64 , p < .04 ) , indicating that small si amplitude was associated with a weak sici ( table 2 ) . icf and sef parameters did not correlate at t1 . at t2 , icf in the lh correlated with the s1 amplitude of lh ( r = .65 , p in addition , icf in the nh correlated ( r = .82 , p < .001 ) with the si finger representation area of the lh ; this correlation remained significant also after bonferroni correction ( table 2 ) . moreover , icf in the lh at t1 was correlated ( r = .83 ; p < .002 ) with the si finger representation area of lh at t2 ; high icf at t1 resulted in a small hand representation area at t2 ( figure 1(c ) ) . our study is the first to compare meg and ntms excitability parameters during stroke recovery . navigated tms , not applied previously in longitudinal studies of stroke patients , enabled the precise replication of the stimulus site between separate measurements , adding reliability to the follow - up . we found correlations between cortical excitability estimates derived from ntms and meg . as expected , we found correlations between mt and erd , but in only one of the four possible intrahemispheric and two out of four interhemispheric conditions . the sici and beta ers , both attributed to gabaergic mechanisms , were correlated in one of their four possible intrahemispheric conditions ( in the nh at t2 ) . one reason for this may be that various gaba - a receptor subtypes contribute to sici . nonselective gaba - a receptor activators modify sici whereas the gaba - a1 receptor specific zolpidem did not . nonselective gaba - a agonist zopiclone increased meg beta activity whereas zolpidem suppressed beta activity in the vicinity of stroke lesion . moreover , in healthy subjects , diazepam increased meg erd but did not affect ers when the increase of baseline beta activity was taken into account . this nonspecificity could contribute to the correlations of sici with the erd and mt as well . correlations between ntms parameters and meg erd / ers were stronger at t2 than at t1 . analogously , most tms intracortical excitability measures did not correlate with the hand function acutely but did so 3 months after stroke . recovery of sensorimotor fmri activation to digit stimulation from 1 to 3 months was correlated with final motor function , emphasizing the importance of this time period for stroke recovery . is attributed mainly to glutaminergic mechanisms , glutamate may contribute to stroke - induced plasticity . somewhat surprisingly , high icf at t1 correlated with small si hand area at t2 ( figure 1(c ) ) ; thus , the narrowing towards normal hand representation size may be supported by glutaminergic activity . icf did not correlate with the meg erd / ers , and the si hand area and beta erd / ers were not correlated ; this suggests different mechanisms underlying sici and icf ( see   for a detailed discussion ) . for example , high mt was associated with a small erd in the opposite hemisphere , and strong erd in the lh was associated with a strong sici in the nh . increased excitability within the unaffected motor cortex may cause imbalance between the homologous cortical motor areas and worsen also the ipsilesional hand coordination ( for references , see ) . thus , some functional correlations may relate to the modified general excitability properties of the motor system , instead of effects in the immediate vicinity of the stroke . tms results give direct information of the changes in the motor output and the immediate effects of tms are relatively local . however , also subcortical and spinal processes affect the meps used to evaluate the tms effects . meg reveals the activity of the whole cortical mantle and enables mapping of network effects generated by stroke . meg source analysis suggests mainly motor cortex origin of beta ers [ 13 , 33 , 34 ] . however , in electrocorticography , recorded directly from the cortex , beta erd and ers appear outside of pre- and postcentral gyri , in supplementary motor cortex , or broadly from pre- and postcentral gyri , frontolateral and medial cortex [ 37 , 38 ] . the widespread cortical generation of the erd and ers may make them resilient to small cortical strokes . multitude of generators may contribute to considerable variability of source locations of beta erd in stroke patients ( cf . ) . multiple sources underlying meg signals may also explain resilience of auditory evoked fields after small strokes . stronger correlations between icf and si parameters than between mt and sici and ers / erd may , in part , result from spatially more limited source areas of s1 responses than those of erd / ers . it can be expected that meg and ntms produce complementary information about the effects of stroke on cortical networks . moreover , meg parameters in the affected hemisphere and ntms indices in the unaffected hemisphere were correlated with the motor performance of the affected hand ( cf . [ 18 , 21 , 24 ] ) . erd in the 822  hz band may reflect downregulation of intracortical inhibition in the human motor cortex , as tms delivered during erd is associated with increased mep amplitudes and reduced sici . however , 1  hz repetitive tms over the motor cortex reduces meps to subsequent single tms pulses , indicating inhibition , but decreases postmovement beta ers , and intermittent theta burst tms facilitates meps but increases postmovement beta ers . beta ers is reduced in patients with myoclonus epilepsy , indicating increased cortical excitability . in line , sici is decreased in myoclonus epilepsy patients ; however , mt is increased [ 44 , 45 ] , and the silent period after the tms pulse , reflecting motor cortical postsynaptic inhibition , is prolonged , indicating prevailing inhibitory cortical tonus . thus , only some aspects of the cortical excitability may be shared in excitability estimates obtained by tms and meg . our results suggest that some tms and meg excitability measures reflect the activity of the same transmitter systems . however , high mt and absence of erd / ers may also correlate because of severely affected sensorimotor connections between the periphery and the cortex . we detected sefs in 12/13 patients and meps in 11/13 patients already at t1 , indicating that both somatosensory and motor pathways were conveying signals . motor function can be maintained despite significant damage to the corticospinal tract , as estimated from mt of stroke patients . moreover , we observed fewer correlations at t1 , when the sensorimotor pathways probably were more affected , than at t2 . however , such spurious correlations should remain stable or decrease during recovery from t1 to t2 but not increase , as in our data . the limitations of our study include the small size of the patient group as the precise features of structural and functional changes may differ among the patients . cortical excitability is modified differently in cortical and subcortical strokes [ 46 , 47 ] . this , however , should not alter our correlations between the tms and meg , as both were recorded from the same patients . possible effects of medication on excitability should go in parallel for meg and ntms , as the patients were tested sequentially during the same day . the patients were not tested in the acute stage with tms , and meg recordings showed most dramatic erd and ers modifications between the acute phase and t1 . although mt in the lh is correlated with the paretic hand function in acute stroke , this correlation , however , weakens during recovery , and tms intracortical excitability parameters correlated with the clinical performance best at 3 months . the 2  ms or 12  ms isis , selected for our paired - pulse stimuli , produce clear sici and icf in healthy subjects   and in stroke patients , but we did not test other parameters , which could have produced stronger correlations between ntms and meg . icf and si response amplitude and area size , mt and the erd of the hemisphere harboring the stroke lesion , and sici and ers of the nonlesioned hemisphere are correlated in stroke patients . numerous correlations of the excitability parameters between the lh and nh emphasize the importance of the hemispheric balance of the excitatory - inhibitory properties of the sensorimotor system in analyzing the stroke - related dysfunction during stroke recovery .
objective . 
 stroke alters cortical excitability both in the lesioned and in the nonlesioned hemisphere . 
 stroke recovery has been studied using transcranial magnetic stimulation ( tms ) . 
 spontaneous brain oscillations and somatosensory evoked fields ( sefs ) measured by magnetoencephalography ( meg ) are modified in stroke patients during recovery . 
 methods . 
 we recorded sefs and spontaneous meg activity and motor threshold ( mt ) short intracortical inhibition ( sici ) and intracortical facilitation ( icf ) with navigated tms ( ntms ) at one and three months after first - ever hemispheric ischemic strokes . 
 changes of meg and ntms parameters attributed to gamma - aminobutyrate and glutamate transmission were compared . 
 results . 
 icf correlated with the strength and extent of sef source areas depicted by meg at three months . 
 the ntms mt and event - related desynchronization ( erd ) of beta - band meg activity and sici and the beta - band meg event - related synchronization ( ers ) were correlated , but less strongly . conclusions . 
 this first report using sequential ntms and meg in stroke recovery found intra- and interhemispheric correlations of ntms and meg estimates of cortical excitability . 
 icf and sef parameters , mt and the erd of the lesioned hemisphere , and sici and ers of the nonlesioned hemisphere were correlated . 
 covarying excitability in the lesioned and nonlesioned hemispheres emphasizes the importance of the hemispheric balance of the excitability of the sensorimotor system .