Katja Stefan

Mechanisms of enhancement of human motor cortex excitability induced by interventional paired associative stimulation

Associative stimulation has been shown to enhance excitability in the human motor cortex ( Stefan et al. 2000 ); however, little is known about the underlying mechanisms. An interventional paired associative stimulation (IPAS) was employed consisting of repetitive application of single afferent electric stimuli, delivered to the right median nerve, paired with single pulse transcranial magnetic stimulation (TMS) over the optimal site for activation of the abductor pollicis brevis muscle (APB) to generate approximately synchronous events in the primary motor cortex. Compared to baseline, motor evoked potentials (MEPs) induced by unconditioned, single TMS pulses increased after IPAS. By contrast, intracortical inhibition, assessed using (i) a suprathreshold test TMS pulse conditioned by a subthreshold TMS pulse delivered 3 ms before the test pulse, and (ii) a suprathreshold test TMS pulse conditioned by afferent median nerve stimulation delivered 25 ms before the TMS pulse, remained unchanged when assessed with appropriately matching test stimulus intensities. The increase of single‐pulse TMS‐evoked MEP amplitudes was blocked when IPAS was performed under the influence of dextromethorphan, an N‐methyl‐d‐aspartate (NMDA) receptor antagonist known to block long‐term potentiation (LTP). Further experiments employing the double‐shock TMS protocol suggested that the afferent pulse, as one component of the IPAS protocol, induced disinhibition of the primary motor cortex at the time when the TMS pulse, as the other component of IPAS, was delivered. Together, these findings support the view that LTP‐like mechanisms may underlie the cortical plasticity induced by IPAS.

Formation of a motor memory by action observation

Mirror neurons discharge with both action observation and action execution. It has been proposed that the mirror neuron system is instrumental in motor learning. The human primary motor cortex (M1) displays mirror activity in response to movement observation, is capable of forming motor memories, and is involved in motor learning. However, it is not known whether movement observation can lead directly to the formation of motor memories in the M1, which is considered a likely physiological step in motor learning. Here, we used transcranial magnetic stimulation (TMS) to show that observation of another individual performing simple repetitive thumb movements gives rise to a kinematically specific memory trace of the observed motions in M1. An extended period of observation of thumb movements that were oriented oppositely to the previously determined habitual directional bias increased the probability of TMS-evoked thumb movements to fall within the observed direction. Furthermore, the acceleration of TMS-evoked thumb movements along the principal movement axis and the balance of excitability of muscle representations active in the observed movements were altered in favor of the observed movement direction. These findings support a role for the mirror neuron system in memory formation and possibly human motor learning.

Encoding a motor memory in the older adult by action observation.

The ability of motor training to encode a motor memory is reduced in older adults. Here, we tested the hypothesis that training-dependent memory encoding, an issue of relevance in neurorehabilitation, is enhanced in elder individuals by action observation which alone can contribute to learning processes. A group of 11 healthy older adults participated in this study, which consisted of three randomized counterbalanced sessions on different days testing the effects of motor training (MT) alone, action observation (AO) alone, and a combination of both (MT + AO) on motor memory encoding. The combination of MT + AO formed a motor memory in the primary motor cortex and differentially modulated motor cortical excitability in muscles that were agonist and antagonist with respect to the training task, but MT or AO alone did not. These results suggest that action observation can enhance the effects of motor training on memory encoding protocols in the older adult, possibly through Hebbian modulation of intracortical excitatory mechanisms.

Cutaneomotor integration in humans is somatotopically organized at various levels of the nervous system and is task dependent

Abstract Integration of tactile afferent signals with motor commands is crucial for the performance of purposeful movements such as during manipulation of an object in the hand. To study the somatotopic organization of sensorimotor integration we applied electrical peripheral conditioning stimuli to a digit located near (homotopic stimulation) or distant from (heterotopic stimulation) relaxed or isometrically contracted intrinsic hand muscles at variable time intervals prior to transcranial magnetic stimulation (TMS). Cutaneous stimulation has previously been shown to modulate the amplitude of the motor evoked potential (MEP) and to shorten the duration of the silent period (SP) evoked by TMS. In relaxed target muscles the time-dependent modulation of TMS-evoked motor responses by homotopic conditioning stimulation differed from modulation by heterotopic stimulation. Similar differences in the modulation pattern evoked by homotopic and heterotopic conditioning stimulation were observed for two distinct target muscles of the hand (abductor digiti minimi, abductor pollicis brevis muscle). Differences in modulation were maximal when the conditioning stimulation was applied 25–30 ms and 150–200 ms prior to TMS. Comparison of the modulation of the amplitudes of MEPs evoked by transcranial electrical stimulation (TES) and the modulation of those evoked by TMS suggests that differences between homotopic and heterotopic stimulation originate subcortically at 25- to 30-ms and, at least partially, cortically at 150- to 200-ms interstimulus intervals. In isometrically contracted intrinsic hand muscles the degree to which the SP was shortened reflected the location and the timing of the conditioning stimulus. Shortening was maximal when the conditioning stimulus was applied nearest to the contracted target muscle and 20 ms prior to the test stimulus. In contrast to the SP duration, the MEP size in voluntarily contracted target muscles was unaffected by the location of the conditioning stimulus. The somatotopic gradient of SP shortening was abolished when the two target muscles were simultaneously activated isometrically. Together, our findings suggest that somatotopy of input-output relationships is implemented at both a spinal and a cortical level in the human central nervous system and may also depend on the motor task involved.

Concurrent action observation modulates practice-induced motor memory formation

Motor practice is associated with the formation of elementary motor memories. Here we tested in human subjects the hypothesis that observation of a motor training associated with physical practice will modulate the encoding process of a motor memory relative to physical practice alone. Voluntary thumb motions were practiced (i) alone in a direction opposite to the baseline direction of transcranial magnetic stimulation (TMS)‐evoked movements (physical practice, PP) and in combination with observation of synchronous movements that were either (ii) directionally congruent (same direction, PP + AOc) or (iii) non‐congruent (opposite direction, PP + AOnc) to the practiced ones. We evaluated the following measures of motor memory formation: percentage of TMS‐evoked thumb movements falling in the direction of practiced motions, acceleration of TMS‐evoked movements along the principal movement axis and corticomuscular excitability of training muscles as indexed by motor‐evoked potential amplitudes. Both PP and PP + AOc, but not PP + AOnc, significantly increased the percentage of TMS‐evoked movements falling in the practiced direction, changed the compound acceleration vector into the trained direction and enhanced the motor‐evoked potential amplitudes in the training agonist muscle. The percentage of TMS‐evoked movements falling in the practiced direction increased significantly more after PP + AOc than after PP. Across all measures of motor memory formation, PP + AOc was most efficacious, followed by PP and PP + AOnc. Action observation modulates practice effects on formation of a motor memory. Strengthening of the process of motor memory encoding depends on the directional congruency of the observed model.

Chapter 59 Paired associative stimulation

Paired associative stimulation (PAS) refers to a paradigm consisting of slow-rate repetitive low-frequency median nerve stimulation combined with transcranial magnetic stimulation (TMS) over the contralateral motor cortex. This protocol has been shown to induce plastic changes of excitability in the human motor cortex. Its principles of design were shaped after associative long-term potentiation (LTP) in experimental animals, a cellular mechanism likely to be relevant for learning and memory. PAS-induced changes of cortical excitability share a number of physiological properties with LTP. Of particular importance is the fact that the sign of PAS-induced changes of the size of amplitudes of the motor evoked potentials (MEPs) depends on the exact interval between the afferent and the magnetic pulse during the intervention. A number of observations suggest that PAS-induced excitability changes may have functional significance. PAS-induced plasticity may contribute to elucidating the pathogenesis of neurological disorders where neuroplasticity is thought to have a pathogenetic role. Finally, PAS-induced plasticity may itself have therapeutic potential.

Effects of riluzole on cortical excitability in patients with amyotrophic lateral sclerosis.

2 Using transcranial magnetic stimulation, the effect of riluzole (RLZ) on cortical excitability was studied in patients with amyotrophic lateral sclerosis (ALS). Paired‐pulse inhibition (PPI) and paired‐pulse facilitation (PPF) were reduced. RLZ partially restored deficient PPI in the first of 4 consecutive 3‐month periods of testing, but left PPF unchanged. These findings substantiate the view that attenuation of glutamate‐related excitotoxicity is an important factor contributing to the beneficial effect of RLZ in ALS. Ann Neurol 2001;49:537–540

Task-dependent modulation of inhibitory actions within the primary motor cortex

Abstract In 11 healthy subjects motor-evoked potentials (MEPs) and silent periods (SPs) were measured in the right first dorsal interosseus (FDI) and abductor pollicis brevis muscles (APB): (1) when transcranial magnetic cortex stimulation (TMS) was applied at tonic isometric contraction of 20% of maximum force, (2) when TMS was applied during tactile exploration of a small object in the hand, (3) when TMS was applied during visually guided goal-directed isometric ramp and hold finger flexion movements, and (4) when at tonic isometric contraction peripheral electrical stimulation (PES) of the median nerve was delivered at various intervals between PES and TMS. Of the natural motor tasks, duration of SPs of small hand muscles was longest during tactile exploration (APB 205±42 ms; FDI 213±47 ms). SP duration at tonic isometric contraction amounted to 172±35 ms in APB and 178±31 ms in FDI, respectively. SP duration in FDI was shortest when elicited during visually guided isometric finger movements (159±15 ms). At tonic isometric contraction, SP was shortened when PES was applied at latencies –30 to +70 ms in conjunction with TMS. The latter effect was most pronounced when PES was applied 20 ms before TMS. PES-induced effects increased with increasing stimulation strength up to a saturation level which appeared at the transition to painful stimulation strengths. Both isolated stimulation of muscle afferents and of low-threshold cutaneous afferents shortened SP duration. However, PES of the contralateral median nerve had no effect on SPs. Amplitudes of MEPs did not change significantly in any condition. Inhibitory control of motor output circuitries seems to be distinctly modulated by peripheral somatosensory and visual afferent information. We conclude that somatosensory information has privileged access to inhibitory interneuronal circuits within the primary motor cortex.

Lymphocyte Subpopulations, Oxidative Burst and Apoptosis in Peripheral Blood Cells of Patients with Multiple Sclerosis–Effect of Interferon-β

At present, the most efficient therapeutical treatment of multiple sclerosis (MS) is achieved by IFN-β. However, its in vivo effects remain incompletely understood. If applied parenterally, the hydrophobic IFN-β acts primarily on blood cells with probable selectivity for functionally different lymphocyte subpopulations, monocytes and granulocytes. We have investigated the expression of the activation marker interleukin-2 receptor-α (CD25) on CD3+ T cells, CD19+ B cells, foetal-type γδ+CD3+ T cells and foetal-type CD5+CD19+ B cells of the peripheral blood. In addition, the oxidative burst activity and apoptosis have been determined in mononuclear and polymorphonuclear blood cells, respectively. The study accompanied a phase III trial with IFN-β1b (BETAFERON®, Schering). Two groups of MS patients with relapsing-remitting course of the disease have been investigated at 8 time points (days 0, 5, 15, 31, 60, 90, 180 and 270 after starting therapy): (1) verum group (n=8) with application of 8 Mill. units IFN-β1b every other day, and (2) placebo group (n=4) with application of placebo for 3 months and therapy as in (1) from day 90 onward. The main results were: (1) Activated T cells decreased until day 180 in the verum group and return thereafter to pre-treatment values, whereas in the placebo group the values remained relatively stable over the whole observation period. (2) Activated B cells increased between days 90 and 270 in both groups, i.e. after verum application in both groups. (3) Foetal-type B cells were more activated than total B and T cells with increase over time in both groups. (4) Foetal-type T cells exerted relatively stable intra-individual levels with generally low CD25 expression, but punctual CD25 peaks in both groups. (5) The spontaneous oxidative burst was higher in lymphocytes, more variable in monocytes and faster increasing in granulocytes in the verum group than in the placebo group. (6) Apoptosis of mononuclear cells and granulocytes showed similar variations in the verum and placebo groups with the exception of a selective increase over time of the proportion of granulocytes undergoing induced apoptosis in the verum group. It is concluded that IFN-β has the following main effects on the immune system of MS patients: (1) the T cell immunity is systemically and reversibly suppressed, (2) the foetal-type lymphocytes, which are responsible for the first line of defence of infections, are stimulated in the long range, (3) the oxidative burst activity is increased in lymphocytes and granulocytes and instable in monocytes, and (4) the inducibility of apoptosis in granulocytes is increased. Re-examination of the altered blood cell parameters after long-term IFN-β therapy is warranted.

Magnetische Theta-Burst Stimulation: Rolle der vorangehenden Aktivierung des Motorkortex

Die Applikation von kontinuierlicher Theta-Burst Stimulation (cTBS), einem neuen Protokoll der repetitiven transkraniellen Magnetstimulation (TMS), uber dem primaren Motorkortex kann die kortikospinale Exzitabilitat fur mehrere Minuten herabsetzen (Huang et al., 2005). Wir stellten uns die Frage, zu welchem Grad die Wirkung von cTBS von dem vorhergehenden Aktivierungszustand des konditionierten Motorkortex abhangig ist. Es wurde die Wirkung von funf verschiedenen Interventionen auf die Amplitude der motorischen evozierten Potenziale (MEPs) des rechten M. abductor pollicis brevis (APB) nach einzelnen TMS Reizen uber dem linken M1 bis zu 24 Minuten nach der Intervention untersucht. In den Experimenten 1 bis 3 wurden schwache (25% der maximalen Kraft), isometrische Kontraktionen des APB Muskels fur eine Dauer von 0min (ACT0), 1,5min (ACT1,5) und 5min (ACT5) durchgefuhrt. Daraufhin wurden hochfrequente (50Hz) Folgen von drei TMS Reizen in 5Hz Intervallen fur 20s uber dem linken M1 bei einer Intensitat von 70% der Ruheschwelle (cTBSRMT) appliziert. Experiment 4 war identisch zu ACT0+TBSRMT, mit dem einzigen Unterschied, dass die Stimulationsintensitat auf 80% der aktiven Schwelle (TBSAMT) gesetzt wurde. In Experiment 5 fuhrten die Probanden ohne anschliesende Intervention eine funfminutige isometrische Kontraktion durch (ACT5 ohne TBS). Nach ACT0+TBSRMT konnte keine Veranderung der MEP Amplituden beobachtet werden. ACT5 ohne TBS fuhrte zu einem Anstieg (nach 6min: 130±22%; p=0,005), wahrend durch ACT1,5+TBSRMT (nach 2min: 71±22%; p=0,019; nicht aber nach 6min: 100±36%; p=0,496), ACT5+TBSRMT (nach 6min: 65±26%; p=0,004) und TBSAMT (nach 6min: 75±23%; p=0,015) die MEP Amplituden vermindert wurden (ANOVA; ZEIT*INTERVENTION: F=1,573; p=0,012). Die Reduktion der MEP Amplituden war bei langerer Voraktivierung ausgepragter. Die Verminderung der kortikospinalen Exzitabilitat durch cTBS ist abhangig von der vorangehenden Aktivierung des Zielkortex. Diese Ergebnisse sind relevant fur die Anwendung von cTBS als eine „virtuelle Lasions-“Technik. Ref.: Huang YZ, Edwards MJ, Rounis E, Bhatia KP, Rothwell JC. Theta burst stimulation of the human motor cortex. Neuron. 2005 Jan 20;45(2):201–6. Unterstutzt durch gemeinnutzige Hertie-Stiftung, Deutschland.