Paired Associative Stimulation Protocol Research Articles

Influence of frontal-to-parietal connectivity in pseudoneglect: A cortico-cortical paired associative stimulation study

Pseudoneglect is a set of visuospatial biases that entails a behavioral advantage for stimuli appearing in the left hemifield compared to the right one. Although right hemisphere dominance for visuospatial processing has been invoked to explain this phenomenon, its neurophysiological mechanisms are still debated, and the role of intra- and inter-hemispheric connectivity is yet to be defined. The present study explored the possibility of modulating pseudoneglect in healthy participants through a cortico-cortical paired associative stimulation protocol (ccPAS): a non-invasive brain stimulation protocol that manipulates the interplay between brain regions through the repeated, time-locked coupling of two transcranial magnetic stimulation (TMS) pulses. In the first experiment, healthy participants underwent a frontal-to-parietal (FP) and a parietal-to-frontal (PF) ccPAS. In the FP protocol, the first TMS pulse targeted the right frontal eye field (FEF), and the second pulse the right inferior parietal lobule (IPL), two critical areas for visuospatial and attentional processing. In the PF condition, the order of the pulses was reversed. In both protocols, the inter-stimulus interval (ISI) was 10 ms. Before and after stimulation, pseudoneglect was assessed with a landmark task and a manual line bisection task. A second experiment controlled for ccPAS timing dependency by testing FP-ccPAS with a longer ISI of 100 ms. Results showed that after administering the FP-ccPAS with the ISI of 10 ms, participants’ leftward bias in the landmark task increased significantly, with no effects in the manual line bisection task. The other two protocols tested were ineffective. Our findings showed that ccPAS could be used to modulate pseudoneglect by exploiting frontal-to-parietal connectivity, possibly through increased top-down attentional control. FP-ccPAS could represent a promising tool to investigate connectivity properties within visuospatial and attentional networks in the healthy and as a potential rehabilitation protocol in patients suffering from severe visuospatial pathologies.

Cortico-cortical paired associative stimulation conditioning superficial ventral premotor cortex-primary motor cortex connectivity influences motor cortical activity during precision grip.

The ventral premotor cortex (PMv) and primary motor cortex (M1) represent critical nodes of a parietofrontal network involved in grasping actions, such as power and precision grip. Here, we investigated how the functional PMv-M1 connectivity drives the dissociation between these two actions. We applied a PMv-M1 cortico-cortical paired associative stimulation (cc-PAS) protocol, stimulating M1 in both postero-anterior (PA) and antero-posterior (AP) directions, in order to induce long-term changes in the activity of different neuronal populations within M1. We evaluated the motor-evoked potential (MEP) amplitude, MEP latency and cortical silent period, in both PA and AP, during the isometric execution of precision and power grip, before and after the PMv-M1 cc-PAS. The repeated activation of the PMv-M1 cortico-cortical network with PA orientation over M1 did not change MEP amplitude or cortical silent period duration during both actions. In contrast, the PMv-M1 cc-PAS stimulation of M1 with an AP direction led to a specific modulation of precision grip motor drive. In particular, MEPs tested with AP stimulation showed a selective increase of corticospinal excitability during precision grip. These findings suggest that the more superficial M1 neuronal populations recruited by the PMv input are involved preferentially in the execution of precision grip actions. KEY POINTS: Ventral premotor cortex (PMv)-primary motor cortex (M1) cortico-cortical paired associative stimulation (cc-PAS) with different coil orientation targets dissociable neural populations. PMv-M1 cc-PAS with M1 antero-posterior coil orientation specifically modulates corticospinal excitability during precision grip. Superficial M1 populations are involved preferentially in the execution of precision grip. A plasticity induction protocol targeting the specific PMv-M1subpopulation might have important translational value for the rehabilitation of hand function.

Targeted Modulation of Human Brain Interregional Effective Connectivity With Spike-Timing Dependent Plasticity

ObjectiveThe ability to selectively up- or downregulate interregional brain connectivity would be useful for research and clinical purposes. Toward this aim, cortico-cortical paired associative stimulation (ccPAS) protocols have been developed in which two areas are repeatedly stimulated with a millisecond-level asynchrony. However, ccPAS results in humans using bifocal transcranial magnetic stimulation (TMS) have been variable, and the mechanisms remain unproven. In this study, our goal was to test whether ccPAS mechanism is spike-timing–dependent plasticity (STDP). Materials and MethodsEleven healthy participants received ccPAS to the left primary motor cortex (M1) → right M1 with three different asynchronies (5 milliseconds shorter, equal to, or 5 milliseconds longer than the 9-millisecond transcallosal conduction delay) in separate sessions. To observe the neurophysiological effects, single-pulse TMS was delivered to the left M1 before and after ccPAS while cortico-cortical evoked responses were extracted from the contralateral M1 using source-resolved electroencephalography. ResultsConsistent with STDP mechanisms, the effects on synaptic strengths flipped depending on the asynchrony. Further implicating STDP, control experiments suggested that the effects were unidirectional and selective to the targeted connection. ConclusionThe results support the idea that ccPAS induces STDP and may selectively up- or downregulate effective connectivity between targeted regions in the human brain.

Transcranial Magnetic Stimulation Following a Paired Associative Stimulation Protocol Based on a Video Game Neuromodulates Cortical Excitability and Motor Behavior.

Transcranial Magnetic Stimulation (TMS) can be used to modulate cortico-spinal excitability following a paired associative stimulation (PAS) protocol. Movement-related cortical stimulation (MRCS) is a PAS protocol based on the synchronization of a single-pulse TMS with a movement task. However, plasticity and motor performance potentiation due to MRCS has been related exclusively to single-movement tasks. In order to unveil the effects of an MRCS protocol in complex movements, we applied PAS synchronized with a movement-related dynamic task (MRDT) with a customized video game. In 22 healthy subjects, we measured the reaction time (RT), trajectory error (TE), and the number of collected and avoided items when playing the custom video game to evaluate the task motor performance. Moreover, we assessed the recruitment curve of Motor Evoked Potentials (MEPs) with five different intensities to evaluate the motor corticospinal excitability. MEPs were recorded in Abductor Pollicis Brevis (APB) and Abductor Digiti Minimi (ADM), before, right after, and 30 min after the PAS intervention, in an active versus sham experimental design. The MRCS PAS intervention resulted in RT reduction, and motor corticospinal excitability was modulated, reflected as significant MEP amplitude change at 110% RMT intensity in ADM and at 130% RMT intensity in APB. RTs and ADM MEP amplitudes correlated positively in specific time and intensity assessments. We conclude that the proposed PAS protocol facilitated RT performance in a complex task. This phenomenon might be useful to develop neurorehabilitation strategies with complex movements, similar to activities of daily living.

Human perceptual and metacognitive decision-making rely on distinct brain networks.

Perceptual decisions depend on the ability to exploit available sensory information in order to select the most adaptive option from a set of alternatives. Such decisions depend on the perceptual sensitivity of the organism, which is generally accompanied by a corresponding level of certainty about the choice made. Here, by use of corticocortical paired associative transcranial magnetic stimulation protocol (ccPAS) aimed at inducing plastic changes, we shaped perceptual sensitivity and metacognitive ability in a motion discrimination task depending on the targeted network, demonstrating their functional dissociation. Neurostimulation aimed at boosting V5/MT+-to-V1/V2 back-projections enhanced motion sensitivity without impacting metacognition, whereas boosting IPS/LIP-to-V1/V2 back-projections increased metacognitive efficiency without impacting motion sensitivity. This double-dissociation provides causal evidence of distinct networks for perceptual sensitivity and metacognitive ability in humans.

Neurophysiological assessment of juvenile parkinsonism due to primary monoamine neurotransmitter disorders

No studies have investigated voluntary movement abnormalities and their neurophysiological correlates in patients with parkinsonism due to inherited primary monoamine neurotransmitter (NT) disorders. Nine NT disorders patients and 16 healthy controls (HCs) were enrolled. Objective measurements of repetitive finger tapping were obtained using a motion analysis system. Primary motor cortex (M1) excitability was assessed by recording the input/output (I/O) curve of motor-evoked potentials (MEP) and using a conditioning test paradigm for short-interval intracortical inhibition (SICI) assessment. M1 plasticity-like mechanisms were indexed according to MEPs amplitude changes after the paired associative stimulation protocol. Patient values were considered abnormal if they were greater or lower than two standard deviations from the average HCs value. Patients with aromatic amino acid decarboxylase, tyrosine hydroxylase, and 6-pyruvoyl-tetrahydropterin synthase defects showed markedly reduced velocity (5/5 patients), reduced movement amplitude, and irregular rhythm (4/5 patients). Conversely, only 1 out of 3 patients with autosomal-dominant GTPCH deficiency showed abnormal movement parameters. Interestingly, none of the patients had a progressive reduction in movement amplitude or velocity during the tapping sequence (no sequence effect). Reduced SICI was the most prominent neurophysiological abnormality in patients (5/9 patients). Finally, the I/O curve slope correlated with movement velocity and rhythm in patients. We provided an objective assessment of finger tapping abnormalities in monoamine NT disorders. We also demonstrated M1 excitability changes possibly related to alterations in motor execution. Our results may contribute to a better understanding of the pathophysiology of juvenile parkinsonism due to dopamine deficiency.

Effects of Skin Stimulation on Sensory-Motor Networks Excitability: Possible Implications for Physical Training in Amyotrophic Lateral Sclerosis.

BackgroundMany different trials were assessed for rehabilitation of patients with amyotrophic lateral sclerosis (ALS), with non-unique results. Beside the effects on muscle trophism, some of the encouraging results of physical training could be ascribed to the modulation of cortical excitability, which was found hyperexcited in ALS.ObjectiveThe effects of tactile skin stimulation in the modulation of the sensory-motor integrative networks in healthy subjects were assayed through the paired associative stimulation (PAS) protocol.MethodsIn total, 15 healthy subjects were enrolled. In the standard PAS session, the average amplitude of the motor evoked potential (MEP) after 10 stimuli of transcranial magnetic stimulation (TMS) was measured at the baseline and after the PAS protocol (0, 10, 20, 30, and 60 min). In the skin stimulation session, the average amplitude of the MEP was measured before and after 10 min of skin stimulation over the hand. Subsequently, each subject underwent the PAS stimulation and the measure of the average amplitude of the MEP (0, 10, 20, 30, and 60 min).ResultsThe tactile skin stimulation on healthy subjects increases the PAS-induced sensory-motor network hyperexcitability in healthy subjects.ConclusionSkin stimulation should be avoided in the physiotherapeutic approaches for patients with ALS, given the possible hyperexciting effects on the already upmodulated sensory-motor networks. They can be taken into account for diseases characterized by downregulation of cortical and transcortical networks.

A novel paired associative stimulation protocol with a high-frequency peripheral component: review of results in spinal cord injury rehabilitation. (Part of the symposium "Navigated TMS - based techniques in rehabilitation of motor function: diagnostics, prognostics, therapy", ID 14)

Abstract Background: In recent decades, a multitude of therapeutic approaches has been developed for spinal cord injury (SCI), but few have progressed to regular clinical practice. Novel non-invasive, cost-effective, and feasible approaches to treat this challenging condition are needed. Non-invasive stimulation techniques provide an attractive possibility to activate and strengthen residual neural connections after incomplete SCI. Methods: Paired associative stimulation (PAS) is a combination of transcranial magnetic stimulation (TMS) and peripheral nerve stimulation (PNS). We developed a novel variant of this technique called high-PAS, which consists of high-intensity TMS and high-frequency PNS. This presentation will review our recent clinical results, as well as the results of protocol optimization in healthy subjects. Results: 25 patients with incomplete SCI with wide range of injury severity, age, and time since injury received high-PAS to upper or lower limbs in 4 case series (5 patients each) and 4 case studies. High-PAS sessions to multiple peripheral nerve - motor cortex pairs were applied 3-5 times per week for 4-12 weeks. We documented significant increases in manual motor scores (MMT) of upper and lower limbs, functional hand tests, walking tests, and measures of functional independence in incomplete SCI patients (tetraplegic and paraplegic, traumatic and neurological). We optimized PAS settings in three healthy subject studies (5 experiments in 34 subjects). By now the most optimal protocol is 0.2 Hz PAS with 100 Hz PNS component and TMS given at 100% SO. We also show that this protocol is not highly sensitive to moderate errors in mapping and interstimulus interval determination. Conclusions: High-PAS is a promising new approach for enhancing motor rehabilitation outcomes after incomplete SCI. To confirm clinical results, we are currently conducting a double-blind sham-controlled randomized clinical trial in subacute SCI patients (20 patients). We also continue studies in healthy subjects to further optimize the stimulation protocol. Keywords: paired associative stimulation, spinal cord injury, TMS, peripheral electrical stimulation

Investigating the effects of paired somatosensory - cerebellar stimulation on cortical and cerebellar excitability: a TMS study

Abstract It is well known that paired associative stimulation (PAS) is capable of inducing long term potentiation-like synaptic plasticity when repeated pairings of an electrical stimulus to the median nerve with a transcranial magnetic stimulation (TMS) applied over the motor cortex (M1) is administered between 21-25 ms (Stefan et al., 2000). Interestingly, when PAS is administered at 25 ms, cerebellar activity can abolish PAS after-effects (Hamada et al., 2012). While this suggests that cerebellar activity may influence the arrival of sensory inputs to the sensorimotor cortex, this has not been directly tested using physiological markers of somatosensory and cerebellar inputs to M1 or somatosensory cortex (S1). Since the cerebellum is capable of priming M1 plasticity through the processing of sensory information, we investigated whether the continuous pairing of sensory afferent information with cerebellar stimulation influences the plasticity of both cerebellar and cerebral regions. We tested whether sensory inputs could be paired with cerebellar stimulation to develop a novel PAS protocol. To this aim, electrical stimulation to the median nerve was delivered 10 or 15 ms before applying TMS over the cerebellum (200 paired stimuli). We measured motor evoked potentials (MEPs) and somatosensory evoked potentials (SEPs) as physiological markers of cortical excitability, cerebellum-brain inhibition (CBI) as a marker of cerebellar excitability, and short afferent inhibition (SAI) as a marker of somatosensory inhibition, before and following PAS. Preliminary results showed that sensory-cerebellar PAS significantly modifies M1 excitability, reducing MEP amplitude and increasing SEP amplitude. This effect occurs only when the PAS interval was 10ms, but not at 15ms. Moreover, CBI and SAI were unchanged following PAS. The repetitive pairing of both somatosensory and cerebellar stimulation can induce plasticity effects on cerebral areas. The results of sensory-cerebellar PAS could provide a useful intervention with clinical implications for patients with sensory-motor deficits such as dystonia. Keywords: PAS, Cerebellum, Sensory , TMS

A New Paired Associative Stimulation Protocol with High-Frequency Peripheral Component and High-Intensity 20 Hz Repetitive Transcranial Magnetic Stimulation-A Pilot Study.

Paired associative stimulation (PAS) is a stimulation technique combining transcranial magnetic stimulation (TMS) and peripheral nerve stimulation (PNS) that can induce plastic changes in the human motor system. A PAS protocol consisting of a high-intensity single TMS pulse given at 100% of stimulator output (SO) and high-frequency 100-Hz PNS train, or “the high-PAS” was designed to promote corticomotoneuronal synapses. Such PAS, applied as a long-term intervention, has demonstrated therapeutic efficacy in spinal cord injury (SCI) patients. Adding a second TMS pulse, however, rendered this protocol inhibitory. The current study sought for more effective PAS parameters. Here, we added a third TMS pulse, i.e., a 20-Hz rTMS (three pulses at 96% SO) combined with high-frequency PNS (six pulses at 100 Hz). We examined the ability of the proposed stimulation paradigm to induce the potentiation of motor-evoked potentials (MEPs) in five human subjects and described the safety and tolerability of the new protocol in these subjects. In this study, rTMS alone was used as a control. In addition, we compared the efficacy of the new protocol in five subjects with two PAS protocols consisting of PNS trains of six pulses at 100 Hz combined with (a) single 100% SO TMS pulses (high-PAS) and (b) a 20-Hz rTMS at a lower intensity (three pulses at 120% RMT). The MEPs were measured immediately after, and 30 and 60 min after the stimulation. Although at 0 and 30 min there was no significant difference in the induced MEP potentiation between the new PAS protocol and the rTMS control, the MEP potentiation remained significantly higher at 60 min after the new PAS than after rTMS alone. At 60 min, the new protocol was also more effective than the two other PAS protocols. The new protocol caused strong involuntary twitches in three subjects and, therefore, its further characterization is needed before introducing it for clinical research. Additionally, its mechanism plausibly differs from PAS with high-frequency PNS that has been used in SCI patients.

A novel paired associative stimulation protocol with a high-frequency peripheral component: A review on results in spinal cord injury rehabilitation.

In recent decades, a multitude of therapeutic approaches has been developed for spinal cord injury (SCI), but few have progressed to regular clinical practice. Novel non-invasive, cost-effective, and feasible approaches to treat this challenging condition are needed. A novel variant of paired associative stimulation (PAS), high-PAS, consists of non-invasive high-intensity transcranial magnetic stimulation (TMS) and non-invasive high-frequency electrical peripheral nerve stimulation (PNS). We observed a therapeutic effect of high-PAS in 20 patients with incomplete SCI with wide range of injury severity, age, and time since injury. Tetraplegic and paraplegic, traumatic, and neurological SCI patients benefited from upper- or lower-limb high-PAS. We observed increases in manual motor scores (MMT) of upper and lower limbs, functional hand tests, walking tests, and measures of functional independence. We also optimized PAS settings in several studies in healthy subjects and began elucidating the mechanisms of therapeutic action. The scope of this review is to describe the clinical experience gained with this novel PAS approach. This review is focused on the summary of our results and observations and the methodological considerations for researchers and clinicians interested in adopting and further developing this new method.

Does sonification of action simulation training impact corticospinal excitability and audiomotor plasticity?

Sonification is a sensory augmentation strategy whereby a sound is associated with, and modulated by, movement. Evidence suggests that sonification could be a viable strategy to maximize learning and rehabilitation. Recent studies investigated sonification of action observation, reporting beneficial effects, especially in Parkinson’s disease. However, research on simulation training—a training regime based on action observation and motor imagery, in which actions are internally simulated, without physical execution—suggest that action observation alone is suboptimal, compared to the combined use of action observation and motor imagery. In this study, we explored the effects of sonified action observation and motor imagery on corticospinal excitability, as well as to evaluate the extent of practice-dependent plasticity induced by this training. Nineteen participants were recruited to complete a practice session based on combined and congruent action observation and motor imagery (AOMI) and physical imitation of the same action. Prior to the beginning, participants were randomly assigned to one of two groups, one group (nine participants) completed the practice block with sonified AOMI, while the other group (ten participants) completed the practice without extrinsic auditory information and served as control group. To investigate practice-induced plasticity, participants completed two auditory paired associative stimulation (aPAS) protocols, one completed after the practice block, and another one completed alone, without additional interventions, at least 7 days before the practice. After the practice block, both groups significantly increased their corticospinal excitability, but sonification did not exert additional benefits, compared to non-sonified conditions. In addition, aPAS significantly increased corticospinal excitability when completed alone, but when it was primed by a practice block, no modulatory effects on corticospinal excitability were found. It is possible that sonification of combined action observation and motor imagery may not be a useful strategy to improve corticospinal, but further studies are needed to explore its relationship with performance improvements. We also confirm the neuromodulatory effect of aPAS, but its interaction with audiomotor practice remain unclear.

A Bayesian approach to analysing cortico-cortical associative stimulation induced increases in the excitability of corticospinal projections in humans

Repeated pairing of transcranial magnetic stimulation (TMS) over left and right primary motor cortex (M1), at intensities sufficient to generate descending volleys, produces sustained increases in corticospinal excitability. In other paired associative stimulation (PAS) protocols, in which peripheral afferent stimulation is the first element, changes in corticospinal excitability achieved when the second stimulus consists of brief bursts of transcranial alternating current stimulation (tACS), are comparable to those obtained if TMS is used instead (McNickle and Carson 2015). The present aim was to determine whether associative effects are induced when the first stimulus of a cortico-cortical pair is tACS, or alternatively subthreshold TMS. Bursts of tACS (500 ms; 140 Hz; 1 mA) were associated (180 stimulus pairs) with single magnetic stimuli (120% resting motor threshold rMT) delivered over the opposite (left) M1. The tACS ended 6 ms prior to the TMS. In a separate condition, TMS (55% rMT) was delivered to right M1 6 ms before (120% rMT) TMS was applied over left M1. In a sham condition, TMS (120% rMT) was delivered to left M1 only. The limitations of null hypothesis significance testing are well documented. We therefore employed Bayes factors to assess evidence in support of experimental hypotheses—defined precisely in terms of predicted effect sizes, that these two novel variants of PAS increase corticospinal excitability. Although both interventions induced sustained (~ 20–30 min) increases in corticospinal excitability, the evidence in support of the experimental hypotheses (over specified alternatives) was generally greater for the paired TMS-TMS than the tACS-TMS conditions.

Role of cutaneous and proprioceptive inputs in sensorimotor integration and plasticity occurring in the facial primary motor cortex

Previous studies investigating the effects of somatosensory afferent inputs on cortical excitability and neural plasticity often used transcranial magnetic stimulation (TMS) of hand motor cortex (M1) as a model, but in this model it is difficult to separate out the relative contribution of cutaneous and muscle afferent input to each effect. In the face, cutaneous and muscle afferents are segregated in the trigeminal and facial nerves, respectively. We studied their relative contribution to corticobulbar excitability and neural plasticity in the depressor anguli oris M1. Stimulation of trigeminal afferents induced short-latency (SAI) but not long-latency (LAI) afferent inhibition of face M1, while facial nerve stimulation evoked LAI but not SAI. Plasticity induction was observed only after a paired associative stimulation protocol using the facial nerve. Physiological differences in effects of cutaneous and muscle afferent inputs on face M1 excitability suggest they play separate functional roles in behaviour. The lack of conventional muscle spindles in face muscles raises the question of how sensory input from the face is used to control muscle activation. In 16 healthy volunteers, we probed sensorimotor interactions in face motor cortex (fM1) using short-afferent inhibition (SAI), long-afferent inhibition (LAI) and LTP-like plasticity following paired associative stimulation (PAS) in the depressor anguli oris muscle (DAO). Stimulation of low threshold afferents in the trigeminal nerve produced a clear SAI (P<0.05) when the interval between trigeminal stimulation and transcranial magnetic stimulation (TMS) of fM1 was 15-30ms. However, there was no evidence for LAI at longer intervals of 100-200ms, nor was there any effect of PAS. In contrast, facial nerve stimulation produced significant LAI (P<0.05) as well as significant facilitation 10-30 minutes after PAS (P<0.05). Given that the facial nerve is a pure motor nerve, we presume that the afferent fibres responsible were those activated by the evoked muscle twitch. The F-wave in DAO was unaffected during both LAI and SAI, consistent with their presumed cortical origin. We hypothesize that, in fM1, SAI is evoked by activity in low threshold, presumably cutaneous afferents, whereas LAI and PAS require activity in (higher threshold) afferents activated by the muscle twitch evoked by electrical stimulation of the facial nerve. Cutaneous inputs may exert a paucisynaptic inhibitory effect on fM1, while proprioceptive information is likely to target inhibitory and excitatory polysynaptic circuits involved in LAI and PAS. Such information may be relevant to the physiopathology of several disorders involving the cranio-facial system.

Touch anticipation mediates cross-modal Hebbian plasticity in the primary somatosensory cortex

Paired associative stimulation (PAS) protocols can be used to induce Hebbian plasticity in the human brain. A modified, cross-modal version, of the PAS (cross-modal PAS, cm-PAS) has been recently developed. The cm-PAS consists in the repetitive pairings of a transcranial magnetic stimulation (TMS) pulse over the primary somatosensory cortex (S1) and a visual stimulus depicting a hand being touched; a 20 ms of inter-stimulus interval (ISI) is required to affect S1 plasticity, in turn modulating tactile acuity and somatosensory evoked potentials. The present study explores the role of anticipatory simulation in the cm-PAS efficacy, which could be responsible for such a short ISI. To this aim, we compared the effect of the original, fixed-frequency, cm-PAS to that of a jittered version, in which the time interval between trials was not steady but jittered, hence avoiding the anticipation of the upcoming visual-touch stimulus. Moreover, in the jittered PAS, the ISI between the paired stimulations was varied: it could match the early, somatosensory-driven, activation of S1 (20 ms), or the mirror recruitment of S1 by touch observation (150 ms). Results showed that tactile acuity is enhanced by the fixed-frequency cm-PAS, with an ISI of 20 ms between paired stimulation (visual-touch stimulus and TMS pulse over S1), and also by the jittered cm-PAS but only if the ISI is of 150 ms. These findings suggest that the cm-PAS with a jittered frequency, by preventing an anticipatory pre-activation of S1, delays the timing of the interaction between the visual-touch stimulus and the cortical pulse. On a broader perspective, our study highlights the possible involvement of sensory anticipation, likely through mirror-like simulation mechanisms, in tactile mirroring, as well as its influence of the optimal interval between the afferent and the magnetic pulse during PAS protocols.

Lasting Effects of Low-Frequency Repetitive Transcranial Magnetic Stimulation in Writer's Cramp: A Case Report.

The treatment of writer’s cramp (W’sC) is essentially based on the use of botulinum toxin. However, additional treatments are sometime required to prolong the effects of the toxin, compensate for its progressive loss of efficacy in some subjects, and re-educate handwriting (e.g., rehabilitation strategies). Low-frequency repetitive transcranial magnetic stimulation (rTMS) has been employed to improve W’sC, but with short-lasting and controversial outcomes. We report on the effects of a long-lasting low-frequency rTMS paradigm on W’sC symptoms. A 25-year-old male with a diagnosis of simple W’sC was enrolled in the study. He underwent an objective assessment using the Writer’s Cramp Rating Scale (WCRS) and the 1-min writing test. Further, we recorded muscle activation of the upper limb during handwriting using an EMG wireless system. The patient was provided with 1,200 biphasic magnetic pulses delivered at 1 Hz over the left premotor cortex (PMC), 15 times scheduled every 2 days, thus covering a period of 5 weeks, followed by 10 days of rest. This block of stimulations was practiced other four times, for a period of 6 months. The patient showed a gradual clinical improvement with the progression of the treatments. W’sC symptoms totally disappeared and all the clinical scores showed a significant improvement after rTMS completion. Such improvement lasted up to 1 year after the end of the treatment. Moreover, we detected a long-lasting improvement in sensorimotor plasticity as measured by a paired associative stimulation protocol. Our case suggests that the long-lasting application of 1 Hz rTMS to PMC is a safe and potentially valuable tool to improve W’sC symptoms enduringly, probably by reverting maladaptive plasticity mechanisms within the sensory-motor areas of the hemisphere contralateral to the dystonic hand.

Determinants of Inter-Individual Variability in Corticomotor Excitability Induced by Paired Associative Stimulation.

Transcranial magnetic stimulation (TMS) is a well-established tool in probing cortical plasticity in vivo. Changes in corticomotor excitability can be induced using paired associative stimulation (PAS) protocol, in which TMS over the primary motor cortex is conditioned with an electrical peripheral nerve stimulation of the contralateral hand. PAS with an inter-stimulus interval of 25 ms induces long-term potentiation (LTP)-like effects in cortical excitability. However, the response to a PAS protocol tends to vary substantially across individuals. In this study, we used univariate and multivariate data-driven methods to investigate various previously proposed determinants of inter-individual variability in PAS efficacy, such as demographic, cognitive, clinical, neurophysiological, and neuroimaging measures. Forty-one right-handed participants, comprising 22 patients with amnestic mild cognitive impairment (MCI) and 19 healthy controls (HC), underwent the PAS protocol. Prior to stimulation, demographic, genetic, clinical, as well as structural and resting-state functional MRI data were acquired. The two groups did not differ in any of the variables, except by global cognitive status. Univariate analysis showed that only 61% of all participants were classified as PAS responders, irrespective of group membership. Higher PAS response was associated with lower TMS intensity and with higher resting-state connectivity within the sensorimotor network, but only in responders, as opposed to non-responders. We also found an overall positive correlation between PAS response and structural connectivity within the corticospinal tract, which did not differ between groups. A multivariate random forest (RF) model identified age, gender, education, IQ, global cognitive status, sleep quality, alertness, TMS intensity, genetic factors, and neuroimaging measures (functional and structural connectivity, gray matter (GM) volume, and cortical thickness as poor predictors of PAS response. The model resulted in low accuracy of the RF classifier (58%; 95% CI: 42 − 74%), with a higher relative importance of brain connectivity measures compared to the other variables. We conclude that PAS variability in our sample was not well explained by factors known to influence PAS efficacy, emphasizing the need for future replication studies.

FV 1 Cholinergic brain structure and sensory-afferent modulation of motor cortex excitability

Introduction The basal forebrain provides important output within the cholinergic system. The cholinergic system may also influence the effects of paired associative stimulation (PAS), a plasticity inducing protocol involving paired median nerve and motor cortex stimulation, and short latency afferent inhibition (SAI) in which a median nerve sensory afferent stimulus induces short lasting conditioning effects on motor cortex excitability. The responses to either PAS or SAI can be variable. Here we hypothesized that the basal forebrain structural characteristics, or those of the thalamus as important sensory-afferent relay station with cholinergic input, relate to the functional influence of the cholinergic system measured using PAS or SAI. We therefore asked whether structural variability in these cholinergic brain areas could explain some of that functional variability observed with PAS or SAI. Material and methods Forty healthy volunteers (12 male; mean age 60, range 26–81) underwent a facilitatory PAS protocol with an inter-stimulus interval (ISI) of around 25 ms. An LTP-like facilitatory response was defined as an increase post-PAS of MEP amplitude of at least 10% relative to pre-PAS MEP size. SAI employed median nerve condition of motor cortex stimulation with inhibitory as well as facilitatory ISIs. We obtained T1 MPRAGE sequences on a 3T MRI scanner. MRI data were processed using Statistical Parametric Mapping and the CAT12 Toolbox (http://www.neuro.uni-jena.de/cat/) implemented in Matlab 2015a. Volumes of the basal forebrain were determined using a stereotactic atlas based on combined postmortem MRI and histological examination of cholinergic nuclei. As it is based on the histological examination of a single brain specimen and may not generalize across individuals, we also used volumes of right and left BFCS as obtained from the CAT12 toolbox. We used ANOVA models for group comparisons of responders and non-responders to PAS or SAI. Results Nineteen participants (48%) had an LTP-like response to PAS. Age, sex, or motor thresholds did not predict the PAS response. SAI had inhibitory effects in 80% of participants (n = 32). There was no association between the amount of PAS effects and the SAI response. Basal forebrain and right thalamus volumes were larger in SAI responders while volumes were similar in PAS responders and non-responders. Discussion The results suggest that a larger basal forebrain cholinergic output system, and a larger thalamus as sensory-afferent relay station that receives cholinergic input facilitate the short lasting modulation of motor cortex excitability in the SAI paradigm. This could be because of higher cholinergic tone. The cholinergic system may be less important in longer lasting modulation of motor cortex excitability in the PAS paradigm where an LTP-like response may involve more GABA-ergic neurotransmission.

Effects of Acoustic Paired Associative Stimulation on Late Auditory Evoked Potentials

Paired associative stimulation (PAS), a form of non-invasive cortical stimulation pairing transcranial magnetic stimulation (TMS) with a peripheral sensory stimulus, has been shown to induce neuroplastic effects in the human motor, somatosensory and auditory cortex. The current study investigated the effects of acoustic PAS on late auditory evoked potentials (LAEP) and the influence of tone duration and placebo stimulation. In two experiments, 18 participants underwent a PAS with a 4 kHz paired tone of 400 ms duration using 200 pairs of stimuli (TMS-pulse over the left auditory cortex 45 ms after tone-onset) presented at 0.1 Hz. In Experiment 1 this protocol was contrasted with a protocol using a short paired tone of 23 ms duration (PAS-23 ms vs. PAS-400 ms). In Experiment 2 this PAS protocol was contrasted with sham stimulation (PAS-400 ms-sham vs. PAS-400 ms). Before and after PAS, LAEP were recorded for tones of 4 kHz (same carrier frequency as the paired tone) and 1 kHz as control tone. In Experiment 1, there was a significant difference between LAEP amplitudes of the 4 kHz tone after PAS-23 ms and PAS-400 ms with higher LAEP amplitudes after PAS-23 ms. Before both conditions, no difference could be detected. In Experiment 2 we observed a significant overall decrease in LAEP amplitudes pre to post PAS. Unspecific decreases of LAEP following PAS with a long paired tone (PAS-400 ms) might be related to habituation effects due to repeated presentation of sound stimuli which are not evident for PAS with a short paired tone (PAS-23 ms). Interpreting this result using the concept of temporal integration time allows us to discuss it in the context of spike-timing dependent plasticity.

Altered short-term visual paired associative plasticity in migraine patients between attacks

In healthy volunteers (HVs), we recently observed that the rules of the time-dependent paired-associative plasticity found in the sensorimotor system are valid also for the visual system. With the latter method, here, we have tested whether dysfunctioning associative plasticity might characterize the visual system in patients with episodic migraine without aura (MO), where abnormalities in both inhibitory and excitatory paired-associative sensorimotor plasticity have been observed between attacks (1). In 11 MO between attacks and in 14 HVs, we performed a visual paired associative stimulation (vPAS) protocol by coupling 90 black-and-white checkerboard reversals with low-frequency TMS pulses over the occipital cortex at 2 interstimulus intervals in separate sessions by subtracting or adding 25 ms to the visual evoked potential (VEP) P100 latency. We recorded VEPs (600 sweeps) before, after, and 10-min later each vPAS session. VEPs were partitioned in 6 blocks of 100 sweeps. We analysed VEP N1-P1 first block amplitude and delayed habituation. While vPAS-25 significantly enhanced and vPAS + 25 reduced VEP amplitude habituation in HVs, they both did not significantly change VEP amplitude habituation in MO between attacks. We provide evidence for lack of excitability depressing and enhancing short-term associative plasticity mechanisms within the visual system in interictal migraine.