Paired Associative Stimulation Protocol Research Articles

The assessment of somatosensory cortex plasticity during sleep deprivation by paired associative stimulation.

Many animal studies suggest that during sleep deprivation (SD) synaptic strength should progressively increase, leading to the saturation of the ability to induce long-term potentiation (LTP). Nevertheless, direct evidences about the effects of sustained wakefulness on cortical plasticity in humans are still lacking. The aim of the present study was to assess changes in the ability to induce LTP-like mechanism in humans during a period of SD by means of a paired associative stimulation (PAS) protocol, which combines median nerve stimulation with transcranial magnetic stimulation (TMS) applied over the contralateral somatosensory cortex. During a 41-h SD protocol, 16 healthy subjects, defined as responders to the PAS protocol after a pre-selection session, were involved in 4 experimental sessions (11.00 a.m. and 11.00 p.m. of first and second day) with: a) pre-PAS somatosensory evoked potentials (SEPs) recordings; b) PAS protocol; c) post-PAS SEPs recordings. The effect of PAS on SEPs early components (N20-P25 complex) was assessed. During the first experimental session (without SD) no significant PAS effects on SEPs components amplitude have been found, and large intra- and inter-individual variability have been observed. A lack of significant changes has been observed also in the subsequent sessions. Our results index a low intra- and inter-individual reliability of the PAS protocol, suggesting particular caution when longitudinally evaluating the effect of this technique on cortical plasticity.

Differential modulation of motor cortex plasticity in skill- and endurance-trained athletes.

Extensive evidence exists that regular physical exercise offers neuroplastic benefits to the brain. In this study, exercise-specific effects on motor cortex plasticity were compared between 15 skilled and 15 endurance trained athletes and 8 controls. Plasticity was tested with a paired associative stimulation (PAS) protocol. PAS is a non-invasive stimulation method developed to induce bidirectional changes in the excitability of the cortical projections to the target muscles. Motor cortex excitability was assessed by motor-evoked potentials (MEPs) in the task-relevant soleus muscle, elicited with transcranial magnetic stimulation, before and following PAS. To test for changes at the spinal level, soleus short latency stretch reflexes (SLSR) were elicited before and after PAS. PAS induced a significant (76 ± 83 %) increase in MEP amplitude in the skill group, without significant changes in the endurance (-7 ± 35 %) or control groups (21 ± 30 %). Baseline MEP/post MEP ratio was significantly different between the skill and endurance groups. SLSR remained unchanged after the PAS intervention. The possible reason for differential motor cortex plasticity in skill and endurance groups is likely related to the different training-induced adaptations. The findings of the current study suggest that long-term skill training by skill group induced preferable adaptations in the task-related areas of the motor cortex because increased plasticity is known to enhance motor learning.

Shaping thalamo-cortical plasticity: a marker of cortical pain integration in patients with post-anoxic unresponsive wakefulness syndrome?

The distinctive feature of unresponsive wakefulness syndrome (UWS) is the dissociation between arousal and awareness. Cortico-cortical and thalamo-cortical connectivity and plasticity play a key role in consciousness. UWS patients do not usually show any "cortical" behavioral sign in response to painful stimulation. Nevertheless a "focal conscious" pain perception has been hypothesized. Since defective plasticity and connectivity within pain matrix could be striking mechanisms of non-conscious pain perception and, consequently, of non-cortical responses in UWS subjects, aim of our study was to investigate pain-motor plasticity in such patients through a specific paired laser associative stimulation protocol (L-PAS). We enrolled 10 post-anoxic subjects and 10 healthy controls evaluating clinical and electrophysiological parameters before and after the application of such protocol. Some patient showed a restored pain-motor integration with a partial motor cortex excitability modification. Although we studied a small cohort of post-anoxic UWS patients and the results obtained were short-lasting, L-PAS seems a feasible and suitable technique in order to induce plastic change within pain matrix in some UWS patients, allowing the production of "cortical" responses to painful stimuli, which are signs of at least partially ("focal") preserved consciousness. Cortico-thalamic plasticity could have also an important role in the emergence of pain perception as compared to other sensory modalities.

Sensorimotor Deprivation Induces Interdependent Changes in Excitability and Plasticity of the Human Hand Motor Cortex

Prolonged limb immobilization deprives sensorimotor cortical areas of an important source of excitatory input, as well as of motor output. Previous work has described effects on motor excitability but it is unclear whether motor plasticity is also influenced. In two groups of eight healthy human subjects, the left hand was immobilized for 8 h to induce sensorimotor deprivation of the cortical representation of the abductor pollicis brevis muscle. We used transcranial magnetic stimulation protocols to evaluate motor excitability with motor-evoked potentials, input-output (IOcurve) and short-latency intracortical inhibition (SICI) recruitment curves, as well as long-term potentiation (LTP)/long-term depression (LTD)-like plasticity with paired-associative stimulation (PAS) of the median nerve and motor cortex using an interstimulus interval of 25 ms (PAS25) or 10 ms (PAS10), respectively, in two sessions at least 7 d apart (baseline and after immobilization). After immobilization, the slope of the IOcurve decreased, and SICI at lower conditioning pulse intensities was reduced. The LTP-like effects of PAS25 and the LTD-like effect of PAS10 were both significantly enhanced. The effects differed among individuals: the more IOslope decreased after immobilization, the greater the increase of PAS25 and the smaller the increase of PAS10 effects. We suggest that sensorimotor deprivation has two effects. It increases the sensitivity to remaining sensory inputs and therefore increases the effectiveness of both PAS protocols. In addition, it reduces neuronal excitability to an individually different level, as reflected in the reduced IOslope and leads to an interdependent modulation of synaptic plasticity as such as it shifts the threshold of LTP/LTD-like plasticity induction.

144. Evidence of heterosynaptic interactions in human associative plasticity

Paired associative stimulation (PAS) is a method to study motor cortex synaptic plasticity. If a repetitive electrical stimulus to the median nerve is paired with a transcranial magnetic stimulus (TMS) pulse over the controlateral motor cortex at an interstimulus interval (ISI) of 21.5–25 ms, a long term potentiation (LTP)-like synaptic plasticity is induced in the corticospinal system. We investigated the synaptic spatial specificity of PAS25 and PAS21.5, considered to have similar synaptic mechanisms until recently. Eight subjects (28.6 ± 8.3 years) were selected from a sample of 20 subjects because they showed the expected facilitation after both standard PAS protocols and participated to two sessions in which PAS consisted of 360 electrical stimuli (varPAS) paired with TMS over the hotspot of APB. ISI25 ms (varPAS25) and 21.5 ms (varPAS21.5) were randomly delivered for a total of 360 stimuli. Since cerebellar transcranial direct stimulation (TDCS) can abolish the effects of PAS25, either sham or anodal TDCS (2 mA,30 min) was applied to the cerebellum simultaneously with PAS (anodal-varPAS and sham-varPAS). We measured MEPs before and after each intervention. Randomly delivered PAS25 and PAS21.5 (sham-varPAS) blocked the induction of PAS plasticity while the concurrent anodal TDCS (anodal-varPAS) restored the expected effect. PAS25 and PAS21.5 are inducing LTP-like synaptic plasticity with different synaptic spatial specificity. Heterosynaptic LTD-like modulation might well explain the loss of effect of combining PAS21.5 and PAS25.

Early Visuomotor Integration Processes Induce LTP/LTD-Like Plasticity in the Human Motor Cortex

To investigate whether visuomotor integration processes induce long-term potentiation (LTP) and depression (LTD)-like plasticity in the primary motor cortex (M1), we designed a new paired associative stimulation (PAS) protocol coupling left primary visual area (V1) activation achieved by hemifield visual evoked potentials (VEPs) and transcranial magnetic stimulation (TMS) over the left M1, at specific interstimulus intervals (ISIs), delivered at 1 Hz (V-PAS). Before and after V-PAS, we measured motor evoked potentials (MEPs). To clarify the mechanisms underlying V-PAS, we tested the effect of 1-Hz repetitive TMS (rTMS), 0.25-Hz V-PAS and rTMS, and a shorter 0.25-Hz V-PAS protocol. To examine V-PAS with contralateral V1 activation, we delivered V-PAS activating the right V1. To clarify whether V-PAS increases V1 activity or parieto- and premotor-to-M1 connectivity, before and after V-PAS, we examined VEPs and MEPs evoked by paired-pulse techniques. V-PAS increased, decreased, or left MEPs unchanged according to the ISI used. After 1-Hz rTMS MEPs decreased. Although 0.25-Hz rTMS elicited no aftereffect, 0.25-Hz V-PAS modulated MEPs according to the ISI used. The short 0.25-Hz V-PAS protocol left MEPs unchanged. Contralateral V-PAS inhibited MEPs. After V-PAS, VEPs remained unchanged and the premotor-to-M1 inhibitory connections decreased. V-PAS induces M1 LTP/LTD-like plasticity by activating premotor-to-motor connections.

P 158. Neural correlates of Hebbian and anti-hebbian spike-timing-dependent plasticity in human: A TMS–EEG combined study

Introduction In a recent work by our group we used transcranial magnetic stimulation (TMS) to repeatedly activate the connection between the posterior parietal cortex (PPC) and the primary motor cortex (M1) of the left dominant hemisphere with a paired associative stimulation (PAS) protocol. By varying inter-pulse interval and the activation of different M1 neuronal populations we were able to induce LTP or LTD-like effects as indexed by Motor Evoked Potentials (MEPs) amplitude modulation that followed either Hebbian or anti-Hebbian temporal rules. Objectives Our aim was to further investigate the effects induced by this cortico-cortical PAS protocol over EEG activity, by means of a TMS–EEG coregistration approach. Materials and methods 13 volunteers underwent our novel PAS protocol. Paired stimuli were applied with PPC-TMS preceding (+5 ms) or following (−5 ms) M1 stimulation. In a third condition, the induced current direction over M1 was changed from postero–anterior (PA) to antero–posterior (AP) and the ISI was set at +5 ms. Eighty single pulse TMS were applied to M1 before and after PAS while continuously acquiring EEG from 21 electrodes and recording MEPs from the first dorsal interosseous muscle. We then analysed (i) functional coupling though event-related coherence (ERcoh) for alpha (8–12 Hz) and beta (13–30 Hz) band, (ii) changes in M1 reactivity through TMS-Evoked Potentials (TEPs) and (iii) MEPs amplitude. Results When PPC preceded M1PA stimulation (+5 ms) MEPs amplitude significantly decreased ( p = 0.001), while there was a concurrent increase in ERcoh for the beta band, topographically restricted to P3–C3 pair ( p = 0.02), representing the closest electrodes to the stimulated regions. TEPs analysis indicated a decrease of those components forming a dipole over left centro-parietal sites peaking at about 13 and 20 ms. When PPC followed M1PA stimulation (−5 ms) an increase in MEPs amplitude was induced (p = 0.01) with a concurrent ERcoh increase in the alpha band for P3–C3 pair ( p = 0.01). TEPs component were again modulated at 13 and 20 ms, with an increased amplitude after PAS administration. The AP condition led to opposite results: an increased MEP amplitude when PPC preceded M1AP stimulation (p). Conclusions These findings shed new light on the cortical mechanisms underlying antithetic learning rules in humans. We found that both post-synaptic long term potentiation or depression are always associated to an increased functional connectivity that exclusively upsurge between the stimulated areas. However, the sign of cortical plasticity in M1 is indexed by different brain oscillation activities in the alpha and beta bands. Finally distinct plastic changes differently modulate M1 reactivity as indexed by opposite changes of TEPs amplitude.

P 73. Cortical plasticity and cortical excitability in patients with unilateral severe stenosis/occlusion of the internal carotid artery

Occlusive processes of the internal carotid artery (ICA) lead to chronic hypoperfusion on the affected side. Severe ICA-stenosis and ICA-occlusion are associated with impaired cognition; but the underlying mechanisms are not fully understood ( Balucani and Silvestrini, 2011 ), and neurophysiological alterations of cortical function in chronic hypoperfusion are poorly investigated so far. To study the effect of hypoperfusion on cortical plasticity and cortical excitability in patients with severe ICA-stenosis on both affected and unaffected side. 10 Patients (61 ± 14 years, range 30–74 years, 3 females) with severe unilateral ICA-stenosis ( n = 3) or ICA-occlusion ( n = 7) were included. Severe hypoperfusion on the affected side was diagnosed by transcranial doppler sonography. Using transcranial magnetic stimulation, cortical excitability was assessed bilaterally by resting motor threshold (rMT), GABAB-activity in the cerebral cortex by the cortical silent period (CSP) at 120% and 130% rMT bilaterally, long term potentiation (LTP)-like cortical plasticity using a paired associative stimulation (PAS) protocol bilaterally, comparing motor evoked potentials (MEP) before, and 0, 15 and 30 min after PAS. For all experiments, the investigator was blinded to the side of the stenosis. rMT was significantly lower on the side of the stenosis, as compared to the contralateral side ( p = 0.02). CSP at 120% rMT showed a trendwise decrease on the side of the stenosis, as compared to the contralateral side ( p = 0.06) ( Fig. 1 ). With regard to cortical plasticity, a repeated measures ANOVA revealed a significant interaction of STENOSIS X TIME ( F = 4.05, p = 0.02), and main effect of STENOSIS ( F = 9.51, p = 0.018). Post-hoc t -tests revealed significant differences in favour of the side contralateral to the stenosis at time point T1 (p). As reported previously ( List et al., 2012 ), LTP-like cortical plasticity was decreased in chronic hypoperfusion. Moreover, we demonstrated enhanced cortical excitability on the side of the stenosis, possibly due to reduced cortical inhibitory GABA-activity. Further evaluations (structural MRI, motor learning tests, neuropsychological tests in both patients and age-matched healthy controls; all ongoing) will help elucidate the complex relationship between hypoperfusion, cortical excitability and cortical plasticity, and cognition.

Secondary and primary dystonia: pathophysiological differences

Primary dystonia is thought to be a disorder of the basal ganglia because the symptoms resemble those of patients who have anatomical lesions in the same regions of the brain (secondary dystonia). However, these two groups of patients respond differently to therapy suggesting differences in pathophysiological mechanisms. Pathophysiological deficits in primary dystonia are well characterized and include reduced inhibition at many levels of the motor system and increased plasticity, while emerging evidence suggests additional cerebellar deficits. We compared electrophysiological features of primary and secondary dystonia, using transcranial magnetic stimulation of motor cortex and eye blink classical conditioning paradigm, to test whether dystonia symptoms share the same underlying mechanism. Eleven patients with hemidystonia caused by basal ganglia or thalamic lesions were tested over both hemispheres, corresponding to affected and non-affected side and compared with 10 patients with primary segmental dystonia with arm involvement and 10 healthy participants of similar age. We measured resting motor threshold, active motor threshold, input/output curve, short interval intracortical inhibition and cortical silent period. Plasticity was probed using an excitatory paired associative stimulation protocol. In secondary dystonia cerebellar-dependent conditioning was measured using delayed eye blink classical conditioning paradigm and results were compared with the data of patients with primary dystonia obtained previously. We found no difference in motor thresholds, input/output curves or cortical silent period between patients with secondary and primary dystonia or healthy controls. In secondary dystonia short interval intracortical inhibition was reduced on the affected side, whereas it was normal on the non-affected side. Patients with secondary dystonia had a normal response to the plasticity protocol on both the affected and non-affected side and normal eye blink classical conditioning that was not different from healthy participants. In contrast, patients with primary dystonia showed increased cortical plasticity and reduced eye blink classical conditioning. Normal motor cortex plasticity in secondary dystonia demonstrates that abnormally enhanced cortical plasticity is not required for clinical expression of dystonia, and normal eye blink conditioning suggests an absence of functional cerebellar involvement in this form of dystonia. Reduced short interval intracortical inhibition on the side of the lesion may result from abnormal basal ganglia output or may be a consequence of maintaining an abnormal dystonic posture. Dystonia appears to be a motor symptom that can reflect different pathophysiological states triggered by a variety of insults.

Hebbian and Anti-Hebbian Spike-Timing-Dependent Plasticity of Human Cortico-Cortical Connections

Learning of new skills may occur through Hebbian associative changes in the synaptic strength of cortical connections [spike-timing-dependent plasticity (STDP)], but how the precise temporal relationship of the presynaptic and postsynaptic inputs determines the STDP effects in humans is poorly understood. We used a novel paired associative stimulation protocol to repeatedly activate the short-latency connection between the posterior parietal cortex and the primary motor cortex (M1) of the left-dominant hemisphere. In different experiments, we systematically varied the temporal relationships between the stimuli and the preferential activation of different M1 neuronal populations by applying transcranial magnetic stimulation over M1 with different coil orientations and in different states of cortical excitability (rest vs muscular contraction). We found evidence for the existence of both Hebbian and anti-Hebbian STDP in human long-range connections. The induction of bidirectional long-term potentiation or depression in M1 depended not only on the relative timing between the stimuli but, crucially, on the stimulation of specific neuronal populations and the activity state of the cortex. Our findings demonstrate that these mechanisms are not fixed but susceptible to rapid adaptations. This sudden transition from anti-Hebbian to Hebbian plasticity likely involves local dynamics of interaction with different populations of postsynaptic neurons.

Differences in Dopaminergic Modulation to Motor Cortical Plasticity between Parkinson's Disease and Multiple System Atrophy

Dopamine modulates the synaptic plasticity in the primary motor cortex (M1). To evaluate whether the functioning of the cortico-striatal circuit is necessary for this modulation, we applied a paired associative stimulation (PAS) protocol that comprised an electric stimulus to the right median nerve at the wrist and subsequent transcranial magnetic stimulation of the left M1, to 10 patients with Parkinson's disease (PD) and 10 with multiple system atrophy of the parkinsonian type (MSA-P) with and without dopamine replacement therapy (-on/off). To investigate the M1 function, motor-evoked potentials (MEPs) were measured before and after the PAS. In both patient groups without medication, the PAS protocol failed to increase the averaged amplitude of MEPs. The dopamine replacement therapy in PD, but not in MSA-P effectively restored the PAS-induced MEP increase. This suggests that not the existence of dopamine itself but the activation of cortico-striatal circuit might play an important role for cortical plasticity in the human M1.

A new temporal window for inducing depressant associative plasticity in human primary motor cortex

ObjectiveSpike-timing dependent plasticity (STDP) usually refers to synaptic plasticity induced by near-synchronous activation of neuronal input and neuronal firing. However, some models of STDP predict effects that deviate from this tight temporal synchrony. We aimed to characterise the induction of STDP using paired associative stimulation (PAS) when the pre-synaptic input arrives in primary motor cortex (M1) at (i) intermediate intervals (50–80ms; PAS50,..PAS80) before the post-synaptic neuron is activated and (ii) long intervals (100–450ms; PAS−100,..PAS−450) after the post-synaptic neuron is activated. PAS at near-synchronicity (PAS25) was applied for comparison. MethodsTo characterise the physiological effects of the different PAS protocols, we examined short- and long-interval intra-cortical inhibition; intra-cortical facilitation and short- and long-latency afferent inhibition, in addition to recording MEPs in 45 healthy individuals. ResultsMEP amplitude was reduced at PAS intervals between −250 and −450ms, increased with PAS25, and unaltered at the remaining intervals. There was no change in intra-cortical inhibitory or facilitatory circuits following any PAS protocol. ConclusionsThese findings provide evidence of a previously unreported temporal window in which PAS induces a depression of corticospinal excitability in human M1. SignificanceEstablishing new temporal rules for STDP broadens its applicability for therapeutic usage in future.

Promoting endogenous associative plasticity in human primary motor cortex

Promoting endogenous associative plasticity in human primary motor cortex

Heat-Evoked Experimental Pain Induces Long-Term Potentiation-Like Plasticity in Human Primary Motor Cortex

We designed a new paired associative stimulation (PAS) protocol that combines experimental pain evoked by laser stimuli and transcranial magnetic stimulation (TMS) (Laser-PAS) to primary motor cortex (M1). We tested in healthy subjects whether Laser-PAS elicits cortical plasticity as reflected by long-term changes in motor-evoked potentials (MEPs) (after-effects). In separate experiments, we examined numerous variables including changes induced by varying the interstimulus intervals (ISIs) and Laser-PAS-induced changes in target and non-target muscle MEPs. We measured MEPs after repetitive laser or TMS (rTMS) pulses, and compared magnetic- and electric (TES)-induced MEPs. We tested MEPs after applying Laser-PAS with laser pulses ipsilaterally to M1. Finally, we studied subjects receiving an N-methyl-D-aspartate (NMDA) receptor antagonist (memantine) or placebo (α-lipoic acid). During Laser-PAS at the 50 ms ISI MEPs decreased, thereafter they increased for 60 min; other ISIs induced no after-effects. The after-effects remained restricted to the target muscle. Repetitive laser pulses and rTMS induced no after-effects. After Laser-PAS, TMS-induced MEPs increased, whereas TES-induced MEPs did not. Laser-PAS with laser pulses ipsilaterally to M1 left MEPs unchanged. Memantine, but not α-lipoic acid, abolished the after-effects. In conclusion, Laser-PAS elicits NMDA-dependent cortical plasticity and provides new insights into human pain-motor integration.

Functional Reorganisation in Sensorimotor Cortex Is a Compensatory Mechanism in Early Parkinson's Disease: A Six Months Follow-Up Study (IN6-2.002)

Objective: To study changes in motor cortex plasticity and intracortical inhibition over the early stages of Parkinson9s disease(PD), using Transcranial Magnetic Stimulation. Background In advanced PD motor cortex plasticity and intracortical inhibition are reduced compared to normal if patients are tested off dopaminergic treatment. However, there are no studies investigating how these electrophysiological parameters change with disease progression. Design/Methods: 17 newly diagnosed, clinically asymmetric and drug naive PD patients were studied at baseline. Six months later, measurements were repeated in 13 of them. 6 of the 13 had started treatment with dopaminergic drugs (and were studied after overnight withdrawal), while 7 patients remained untreated. Clinical disease severity was assessed with the motor section of UPDRS scale. 17 healthy participants were included as a control group. EMG recordings were made from APB and ADM muscles. Plasticity was probed in both hemispheres using an excitatory paired associative stimulation (PAS25) protocol. Short-interval intracortical inhibition (SICI) was measured using a paired-pulse paradigm. Results: At baseline, the less affected hemisphere had an increased response to PAS25 with a loss of topographic specificity, both in comparison with the more affected side and with an age matched control group. On the more affected side the response to PAS25 was reduced compared with less affected side and controls. SICI was normal on the less affected side and reduced on the more affected side. Six months later there was no significant change in the UPDRS score in treated and untreated patients. The interhemispheric differences in motor cortex plasticity and the amount of SICI were still evident at 6 months follow-up, and were not different between treated and untreated patients. Conclusions: Increased motor cortical plasticity on the less affected side is consistent with a functional reorganisation of sensorimotor cortex in early PD and may represent a compensatory change that contributes to delaying symptom progression. Supported by: Parkinson9s UK (G-1009). Disclosure: Dr. Kojovic has nothing to disclose. Dr. Kassavetis has nothing to disclose. Dr. Bologna has nothing to disclose. Dr. Berardelli has nothing to disclose. Dr. Rothwell has nothing to disclose. Dr. Edwards has nothing to disclose. Dr. Bhatia has received personal compensation for activities with UCB Pharma, Novartis and Ipsen as a speaker.

Functional reorganization of sensorimotor cortex in early Parkinson disease

Compensatory reorganization of the nigrostriatal system is thought to delay the onset of symptoms in early Parkinson disease (PD). Here we sought evidence that compensation may be a part of a more widespread functional reorganization in sensorimotor networks, including primary motor cortex. Several neurophysiologic measures known to be abnormal in the motor cortex (M1) of patients with advanced PD were tested on the more and less affected side of 16 newly diagnosed and drug-naive patients with PD and compared with 16 age-matched healthy participants. LTP-like effects were probed using a paired associative stimulation protocol. We also measured short interval intracortical inhibition, intracortical facilitation, cortical silent period, and input/output curves. The less affected side in patients with PD had preserved intracortical inhibition and a larger response to the plasticity protocol compared to healthy participants. On the more affected side, there was no response to the plasticity protocol and inhibition was reduced. There was no difference in input/output curves between sides or between patients with PD and healthy participants. Increased motor cortical plasticity on the less affected side is consistent with a functional reorganization of sensorimotor cortex and may represent a compensatory change that contributes to delaying onset of clinical symptoms. Alternatively, it may reflect a maladaptive plasticity that provokes symptom onset. Plasticity deteriorates as the symptoms progress, as seen on the more affected side. The rate of change in paired associative stimulation response over time could be developed into a surrogate marker of disease progression in PD.

Lithium: A switch from LTD- to LTP-like plasticity in human cortex

Lithium, a simple cation, is the mainstay treatment of bipolar disorder. Deficient synaptic plasticity is considered one important mechanism of this disease. Lithium inhibits glycogen synthase kinase-3beta (GSK-3β), which is involved in the regulation of synaptic plasticity. In animal preparations, inhibition of GSK-3β by lithium up-regulated long-term potentiation (LTP) of excitatory synapses but down-regulated long-term depression (LTD). The effects of lithium on plasticity in the human brain are unexplored. We tested the effects of a single oral dose of 900 mg of lithium on LTP-/LTD-like plasticity in human motor cortex induced by established paired associative transcranial magnetic stimulation (PASLTP, PASLTD) protocols. We studied 10 healthy adults in a placebo-controlled double-blind randomized crossover design. PAS-induced plasticity was indexed by change in motor evoked potential amplitude recorded in a hand muscle. In the placebo session, subjects were stratified, according to the known variability of the PASLTP response, into PASLTP ‘LTP responders’ and PASLTP ‘LTD responders’ (n = 5 each). Lithium did not affect the PASLTP-induced LTP-like plasticity in the ‘LTP responders’, but switched the PASLTP-induced LTD-like plasticity in the ‘LTD responders’ to LTP-like plasticity. In contrast, lithium had no effect on the PASLTD-induced LTD-like plasticity in the ‘LTD responders’. We provide first-time evidence that lithium significantly modulates brain stimulation induced plasticity in human cortex. The switch from LTD- to LTP-like plasticity is best explained by the inhibitory action of lithium on GSK-3β. This conclusion is necessarily circumstantial because GSK-3β activity was not directly measured. We discuss that other important plasticity-related modes actions of lithium cannot explain our findings.

Cortical plasticity is preserved in nondemented older individuals with severe ischemic small vessel disease

Ischemic small vessel disease (SVD) is a common finding on routine scans in older people, but cognitive sequelae vary considerably. To improve understanding of mechanisms underlying decline or preservation of cognitive function in this condition, we assessed cognition and cortical plasticity in 20 elderly subjects with severe SVD and 20 age-matched controls without SVD, as rated on conventional MRI. Cognitive status was determined with a neuropsychological test battery, cortical plasticity induced with a paired associative stimulation protocol. Microstructural white matter changes were further analyzed for fractional anisotrophy using diffusion tensor imaging. We found that cortical plasticity as well as memory functions were preserved in severe SVD, while executive functions showed trendwise or significant decreases. Within the SVD group, lower white matter integrity in parahippocampal regions and posterior parts of the corpus callosum was associated with larger cortical plasticity, an association not seen for prefrontal white matter tracts. Enhanced cortical plasticity in subjects with lower white matter integrity in memory-relevant areas might thus indicate a compensatory mechanism to counteract memory decline in severe SVD.

10. Sensorimotor interaction and motor learning in facial muscles

Background and aim : Integration of sensory information with motor output is thought to be important in motor learning. In limb muscles, this is studied using the short afferent inhibition (SAI) paradigm, to assess sensorimotor interaction, and paired associative stimulation (PAS), to evaluate LTP-like plasticity. As far as we know, SAI and PAS paradigms have never been used in the territory of the cranial nerves. The present study was aimed at testing in normal subjects whether sensorimotor interaction and LTP-like plasticity can be observed in facial muscles as well as in limb muscles. Methods : Motor evoked potentials (MEPs) were evoked in the depressor angulis oris (DAO) muscle of 7 subjects. MEPs were recorded from the contralateral DAO at rest and during 10% maximal voluntary contraction (active condition). SAI was tested in 5 subjects, by pairing electrical stimulation (ES, intensity 3 times the perceptual threshold) of the facial nerve, with magnetic stimulation (TMS, 120% of motor threshold intensity) of the facial motor cortex. Intervals between ES and TMS were 5, 10, 15, 20, 25 and 30 ms. The LTP-like plasticity protocol (200 pairs of ES and TMS, 20 ms ISI, at 0.25 Hz) was tested in X subjects by evoking twenty MEPs in both resting and active conditions, before and at 0, 20 and 30 min after paired stimulation. Results : Facial nerve stimulation in the SAI paradigm had no significant affect on MEP amplitude, either in the active or in the relaxed DAO muscle. By contrast MEP amplitude at rest showed a trend of facilitation (p < 0,072) after the PAS protocol administration. When tested at rest this effect was observed at baseline and after 10 min. On the contrary MEP amplitude recorded during activity was significantly enhanced at 10 (p < 0,026) and 30 (p < 0,014) minutes after PAS. There was a significant difference between the time course in resting and active conditions (p < 0,019). Conclusions : These data show that there is no short latency afferent inhibition in the facial motor cortex, yet despite this, there is evidence for maintained LTP-like plasticity. Further studies are needed to understand how and why PAS works in facial muscles despite the absence of SAI. A larger sample is also required to confirm the PAS effect on resting DAO MEPs. A second point to be clarified is why the PAS time course at rest is different from that operating during active condition.

Cerebellum to motor cortex paired associative stimulation induces bidirectional STDP-like plasticity in human motor cortex

The cerebellum is crucially important for motor control and adaptation. Recent non-invasive brain stimulation studies have indicated the possibility to alter the excitability of the cerebellum and its projections to the contralateral motor cortex, with behavioral consequences on motor control and adaptation. Here we sought to induce bidirectional spike-timing dependent plasticity (STDP)-like modifications of motor cortex (M1) excitability by application of paired associative stimulation (PAS) in healthy subjects. Conditioning stimulation over the right lateral cerebellum (CB) preceded focal transcranial magnetic stimulation (TMS) of the left M1 hand area at an interstimulus interval of 2 ms (CB→M1 PAS2 ms), 6 ms (CB→M1 PAS6 ms) or 10 ms (CB→M1 PAS10 ms) or randomly alternating intervals of 2 and 10 ms (CB→M1 PASControl). Effects of PAS on M1 excitability were assessed by the motor-evoked potential (MEP) amplitude, short-interval intracortical inhibition (SICI), intracortical facilitation (ICF) and cerebellar-motor cortex inhibition (CBI) in the first dorsal interosseous muscle of the right hand. CB→M1 PAS2 ms resulted in MEP potentiation, CB→M1 PAS6 ms and CB→M1 PAS10 ms in MEP depression, and CB→M1 PASControl in no change. The MEP changes lasted for 30–60 min after PAS. SICI and CBI decreased non-specifically after all PAS protocols, while ICF remained unaltered. The physiological mechanisms underlying these MEP changes are carefully discussed. Findings support the notion of bidirectional STDP-like plasticity in M1 mediated by associative stimulation of the cerebello-dentato-thalamo-cortical pathway and M1. Future studies may investigate the behavioral significance of this plasticity.