Induction of Human Motor Cortex Plasticity by Theta Burst Transcranial Ultrasound Stimulation.

OBJECTIVE: Transcranial ultrasound stimulation (TUS) is a promising noninvasive brain stimulation technique with advantages of high spatial precision and ability to target deep brain regions. This study aimed to develop a TUS protocol to effectively induce brain plasticity in human subjects. METHODS: An 80-second train of theta burst patterned TUS (tbTUS), regularly patterned TUS (rTUS) with the same sonication duration, and sham tbTUS was delivered to the motor cortex in healthy subjects. Transcranial magnetic stimulation (TMS) was used to examine changes in corticospinal excitability, intracortical inhibition and facilitation, and the site of plasticity induction. The effects of motor cortical tbTUS on a visuomotor task and the effects of occipital cortex tbTUS on motor cortical excitability were also tested. RESULTS: The tbTUS produced consistent increase in corticospinal excitability for at least 30 minutes, whereas rTUS and sham tbTUS produced no significant change. tbTUS decreased short-interval intracortical inhibition and increased intracortical facilitation. The effects of TMS in different current directions suggested that the site of the plastic changes was within the motor cortex. tbTUS to the occipital cortex did not change motor cortical excitability. Motor cortical tbTUS shortened movement time in a visuomotor task. INTERPRETATION: tbTUS is a novel and efficient paradigm to induce cortical plasticity in humans. It has the potential to be developed for neuromodulation treatment for neurological and psychiatric disorders, and to advance neuroscience research. ANN NEUROL 2022;91:238-252.

Quantification of the radiation dose to the pyramidal tract using tractography in treatment planning for stereotactic radiosurgery.

In stereotactic radiosurgery for intracranial lesions, optimization of the dose to the at-risk organs is important to avoid neurological complications. We aimed to quantify the dose to the pyramidal tract (PT) and improve treatment planning for gamma knife radiosurgery by combining tractography. Pyramidal tractography images were depicted in 23 patients with lesions adjacent to the PT and fused with stereotactic magnetic resonance images. We regarded the PT as an at-risk organ and performed dose planning. To assess the efficacy of this process, we compared clinical parameters between plans with and without tractography. In the plans with tractography, the maximum PT dose was significantly reduced, although the irradiation time was prolonged by 3.5 min. There was no significant difference in the dose covering 95% of the lesion volume (D95). This result suggests that the PT dose can be reduced while maintaining the D95 with clinically acceptable prolongation of the irradiation time.

Integration of BOLD-fMRI and DTI into radiation treatment planning for high-grade gliomas located near the primary motor cortexes and corticospinal tracts.

BACKGROUND: The main objective of this study was to evaluate the efficacy of integrating the blood oxygen level dependent functional magnetic resonance imaging (BOLD-fMRI) and diffusion tensor imaging (DTI) data into radiation treatment planning for high-grade gliomas located near the primary motor cortexes (PMCs) and corticospinal tracts (CSTs). METHODS: A total of 20 patients with high-grade gliomas adjacent to PMCs and CSTs between 2012 and 2014 were recruited. The bilateral PMCs and CSTs were located in the normal regions without any overlapping with target volume of the lesions. BOLD-fMRI, DTI and conventional MRI were performed on patients (Karnofsky performance score ≥ 70) before radical radiotherapy treatment. Four different imaging studies were conducted in each patient: a planning computed tomography (CT), an anatomical MRI, a DTI and a BOLD-fMRI. For each case, three treatment plans (3DCRT, IMRT and IMRT_PMC&CST) were developed by 3 different physicists using the Pinnacle planning system. RESULTS: Our study has shown that there was no significant difference between the 3DCRT and IMRT plans in terms of dose homogeneity, but IMRT displayed better planning target volume (PTV) dose conformity. In addition, we have found that the Dmax and Dmean to the ipsilateral and contralateral PMC and CST regions were considerably decreased in IMRT_PMC&CST group (p < 0.001). CONCLUSIONS: In conclusion, integration of BOLD-fMRI and DTI into radiation treatment planning is feasible and beneficial. With the assistance of the above-described techniques, the bilateral PMCs and CSTs adjacent to the target volume could be clearly marked as OARs and spared during treatment.

Differences in brainstem fiber tract response to radiation: a longitudinal diffusion tensor imaging study.

PURPOSE: To determine whether radiation-induced changes in white matter tracts are uniform across the brainstem. METHODS AND MATERIALS: We analyzed serial diffusion tensor imaging data, acquired before radiation therapy and over 48 to 72 months of follow-up, from 42 pediatric patients (age 6-20 years) with medulloblastoma. FSL software (FMRIB, Oxford, UK) was used to calculate fractional anisotropy (FA) and axial, radial, and mean diffusivities. For a consistent identification of volumes of interest (VOIs), the parametric maps of each patient were transformed to a standard brain space (MNI152), on which we identified VOIs including corticospinal tract (CST), medial lemniscus (ML), transverse pontine fiber (TPF), and middle cerebellar peduncle (MCP) at the level of pons. Temporal changes of DTI parameters in VOIs were compared using a linear mixed effect model. RESULTS: Radiation-induced white matter injury was marked by a decline in FA after treatment. The decline was often accompanied by decreased axial diffusivity, increased radial diffusivity, or both. This implied axonal damage and demyelination. We observed that the magnitude of the changes was not always uniform across substructures of the brainstem. Specifically, the changes in DTI parameters for TPF were more pronounced than in other regions (P<.001 for FA) despite similarities in the distribution of dose. We did not find a significant difference among CST, ML, and MCP in these patients (P>.093 for all parameters). CONCLUSIONS: Changes in the structural integrity of white matter tracts, assessed by DTI, were not uniform across the brainstem after radiation therapy. These results support a role for tract-based assessment in radiation treatment planning and determination of brainstem tolerance.

Integration of corticospinal tractography reduces motor complications after radiosurgery.

PURPOSE: To evaluate whether the use of diffusion-tensor tractography (DTT) of the corticospinal tract could reduce motor complications after stereotactic radiosurgery (SRS). METHODS AND MATERIALS: Patients with arteriovenous malformation (AVM) in the deep frontal lobe, deep parietal lobe, basal ganglia, and thalamus who had undergone radiosurgery since 2000 and were followed up for more than 3 years were studied. DTT of the corticospinal tract had been integrated into treatment planning of SRS since 2004, and the maximum dose received by the corticospinal tract was attempted to be less than 20 Gy. Treatment outcomes before (28 patients, Group A) and after (24 patients, Group B) the introduction of this technique were compared. RESULTS: There were no statistical differences between the two groups (Group A vs. Group B) in patients' age (34 years vs. 33 years, p = 0.76), percentage of patients with hemorrhagic events before treatment (50% vs. 29%, p = 0.12), or percentage of AVM involving the basal ganglia and thalamus (36% vs. 46%, p = 0.46). Obliteration rates were 69% and 76% at 4 years in Groups A and B, respectively (p = 0.68), which were not significantly different. Motor complications were observed in 5 patients in Group A (17.9%) but only in 1 patient in Group B (4.2%), which was significantly less frequent (p = 0.021). CONCLUSION: Integrating DTT of the corticospinal tract into treatment planning contributed to reduction of motor complications without compromising the obliteration rate for AVM adjacent to the corticospinal tract.

Integration of functional MRI and white matter tractography in stereotactic radiosurgery clinical practice.

PURPOSE: To study the efficacy of the integration of functional magnetic resonance imaging (fMRI) and diffusion tensor imaging tractography data into stereotactic radiosurgery clinical practice. METHODS AND MATERIALS: fMRI and tractography data sets were acquired and fused with corresponding anatomical MR and computed tomography images of patients with arteriovenous malformation (AVM), astrocytoma, brain metastasis, or hemangioma and referred for stereotactic radiosurgery. The acquired data sets were imported into a CyberKnife stereotactic radiosurgery system and used to delineate the target, organs at risk, and nearby functional structures and fiber tracts. Treatment plans with and without the incorporation of the functional structures and the fiber tracts into the optimization process were developed and compared. RESULTS: The nearby functional structures and fiber tracts could receive doses of >50% of the maximum dose if they were excluded from the planning process. In the AVM case, the doses received by the Broadmann-17 structure and the optic tract were reduced to 700 cGy from 1,400 cGy and to 1,200 cGy from 2,000 cGy, respectively, upon inclusion into the optimization process. In the metastasis case, the motor cortex received 850 cGy instead of 1,400 cGy; and in the hemangioma case, the pyramidal tracts received 780 cGy instead of 990 cGy. In the astrocytoma case, the dose to the motor cortex bordering the lesion was reduced to 1,900 cGy from 2,100 cGy, and therefore, the biologically equivalent dose in three fractions was delivered instead. CONCLUSIONS: Functional structures and fiber tracts could receive high doses if they were not considered during treatment planning. With the aid of fMRI and tractography images, they can be delineated and spared.

Reduced motor cortex plasticity following inhibitory rTMS in older adults.

OBJECTIVE: Ageing is accompanied by diminished practice-dependent plasticity. We investigated the effect of age on another plasticity inducing paradigm, repetitive transcranial magnetic stimulation (rTMS). METHODS: Healthy young (n=15; 25+/-4 years) and old (n=15; 67+/-5 years) adults participated in two experiments. Motor evoked potentials (MEPs) were measured in the target muscle (first dorsal interosseus, FDI) and a remote muscle (abductor digiti minimi) during a set of single stimuli. Subjects then received real or sham inhibitory rTMS (intermittent subthreshold trains of 6Hz stimulation for 10min). MEPs were measured for 30min after rTMS. RESULTS: In young adults, MEPs in the target FDI muscle were approximately 15% smaller in the real rTMS experiment than in the sham rTMS experiment (P<0.026). In old adults, FDI MEP size did not differ between experiments. CONCLUSIONS: Advancing age is associated with reduced efficacy of inhibitory rTMS. SIGNIFICANCE: This work has important implications for the potential therapeutic use of rTMS in stroke and neurological disease.

Breaks during 5Hz rTMS are essential for facilitatory after effects.

OBJECTIVE: Stimulation frequency has been considered the most important factor in conventional repetitive transcranial magnetic stimulation (rTMS) for determining the direction of after effects on corticospinal excitability. Here, we examined the functional relevance of breaks during high-frequency subthreshold rTMS for the induction of facilitatory after effects. METHODS: The after effects on corticospinal excitability of a standard 5Hz rTMS protocol in a block design were compared to a continuous rTMS protocol using the same number of pulses. In addition the effect of current direction both for rTMS and single pulse TMS was included in the study design. RESULTS: While 5Hz rTMS in a standard block design induces facilitatory after effects on corticospinal excitability, the continuous protocol does not induce facilitation but rather inhibition. In our study only rTMS using an initially posterior-anterior current direction in the brain leads to significant neuroplastic effects at all. CONCLUSIONS: Breaks during conventional high-frequency rTMS are a crucial factor determining the direction of induced neuroplastic changes. SIGNIFICANCE: These results contribute to the understanding of rTMS-induced neuroplasticity and are important for the design of rTMS protocols both for experimental and clinical studies.

Defining the mechanisms that underlie cortical hyperexcitability in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis [ALS] is a rapidly progressive neurodegenerative disorder of motor neurons, heralded by the development of cortical hyperexcitability. Reduction of short interval intracortical inhibition [SICI] in ALS, a feature linked to the development of cortical hyperexcitability, may be mediated by degeneration of inhibitory circuits or alternatively activation of high threshold excitatory circuits. As such, determining the mechanisms of SICI reduction in ALS has clear diagnostic and therapeutic significance. Consequently, the present study utilized a novel threshold tracking paired-pulse paradigm to determine whether SICI reduction in ALS represented reduced inhibition or excessive excitation. Using a 90 mm circular coil, SICI was assessed at three different conditioning stimulus intensities: 40%, 70% and 90% of resting motor threshold [RMT]. Motor evoked potential responses were recorded over the abductor pollicis brevis muscle. Short interval intracortical inhibition was uniformly reduced across all three levels of conditioning intensities in ALS [40% RMT, ALS -0.6+/-0.7%, controls 2.0+/-0.6%, P<0.01; 70% RMT, ALS 0.6+/-2.7%, controls 12.8+/-2%, P<0.001; 90% RMT, ALS -15.9+/-1.3%, controls 2.2+/-4.1%, P<0.01]. In addition, the resting motor threshold was reduced, while the motor evoked potential amplitude was increased in ALS patients, in keeping with cortical hyperexcitability. These findings establish that SICI reduction in ALS represents degeneration of inhibitory cortical circuits, combined with excessive excitation of high threshold excitatory pathways. Neuroprotective strategies aimed at preserving the integrity of intracortical inhibitory circuits, in addition to antagonizing excitatory cortical circuits, may provide novel therapeutic targets in ALS.

Recovery of motor disability and spasticity in post-stroke after repetitive transcranial magnetic stimulation (rTMS).

Lately it has been indicated that the stimulation of both sides of the motor cortices with different frequencies of rTMS can improve the behaviour of a paretic arm. We studied the effect of rTMS in severe cases of post-stroke after nearly 10 years. They had wide hemispheric lesion and their paresis had not changed for more than 5 years. The majority of patients could not move their fingers on the affected side. In our study we examined whether the active movement could be induced by rTMS even several years after stroke and which hemisphere (affected or unaffected) stimulated by rTMS would be the best location for attenuating the spasticity and for developing movement in the paretic arm. Sixty-four patients (more than 5 years after stroke in a stable state) were followed for 3 months. They were treated with rTMS with 1 Hz at 30% of 2.3T 100 stimuli per session twice a day for a week. The area to be stimulated was chosen according to the evoked movement by TMS in the paretic arm. That way, four groups were created and compared. In group A, where both hemispheres were stimulated (because of the single stimulation of TMS could induce movement from both sides of hemispheres) the spasticity decreased but the movement could not be influenced. A highly significant improvement in spasticity, in movement induction and in the behaviour of paresis was observed in group B, where before treatment, there was no evoked movement in the paretic arm from stimulating either hemispheres of the brain. For treatment we stimulated the unaffected hemisphere from where the intact arm is moved (ipsilateral to the paretic side). In both groups C (contralateral hemisphere to the paretic arm) and D (ipsilaterally evoked movement in the paretic arm), the spasticity decreased during the first week, but the movement of the paretic arm improved only in group C. It seems that spasticity can be modified by the stimulation either the affected or the unaffected hemisphere, but the induction of movement can be achieved only by the stimulation of an intact motor pathway and its surrounding area (groups B and C). The improvement in paretic extremities can be achieved with rTMS even after years of stroke when the traditional rehabilitation has failed.

Noninvasive stimulation of human corticospinal axons innervating leg muscles.

These studies investigated whether a single electrical stimulus over the thoracic spine activates corticospinal axons projecting to human leg muscles. Transcranial magnetic stimulation of the motor cortex and electrical stimulation over the thoracic spine were paired at seven interstimulus intervals, and surface electromyographic responses were recorded from rectus femoris, tibialis anterior, and soleus. The interstimulus intervals (ISIs) were set so that the first descending volley evoked by cortical stimulation had not arrived at (positive ISIs), was at the same level as (0 ISI) or had passed (negative ISIs) the site of activation of descending axons by the thoracic stimulation at the moment of its delivery. Compared with the responses to motor cortical stimulation alone, responses to paired stimuli were larger at negative ISIs but reduced at positive ISIs in all three leg muscles. This depression of responses at positive ISIs is consistent with an occlusive interaction in which an antidromic volley evoked by the thoracic stimulation collides with descending volleys evoked by cortical stimulation. The cortical and spinal stimuli activate some of the same corticospinal axons. Thus it is possible to examine the excitability of lower limb motoneuron pools to corticospinal inputs without the confounding effects of changes occurring within the motor cortex.

Concurrent excitation of the opposite motor cortex during transcranial magnetic stimulation to activate the abdominal muscles.

The study investigated the potential for stimulation of both motor cortices during transcranial magnetic stimulation (TMS) to evoke abdominal muscle responses. Electromyographic activity (EMG) of transversus abdominis (TrA) was recorded bilaterally in eleven healthy volunteers using fine-wire electrodes. TMS at 120% motor threshold (MT) was delivered at rest and during 10% activation at 1cm intervals from the midline to 5 cm lateral, along a line 2 cm anterior to the vertex. The optimal site to evoke responses in TrA is located 2 cm lateral to the vertex. When bilateral abdominal responses were evoked at or lateral to this site, onset of ipsilateral motor evoked potentials (MEPs) were approximately 3-4 ms longer than contralateral MEPs. The difference between latencies is consistent with activation of faster crossed-, and slower uncrossed-corticospinal pathways from one hemisphere. However, latencies of MEPs were similar between sides when stimulation was applied more medially and were consistent with concurrent activation of crossed corticospinal tracts on both sides. The findings suggest that stimulation of both motor cortices is possible when TMS is delivered less than 2 cm from midline. Concurrent stimulation of both motor cortices can be minimised if TMS is delivered at least 2 cm lateral to midline.

Factors influencing cortical silent period: optimized stimulus location, intensity and muscle contraction.

Inhibitory silent period (SP) is a transient suppression of voluntary muscle activity after depolarization of representative motor neuronal populations following transcranial magnetic stimulation (TMS). Our aim was to evaluate and present an optimal protocol for the measurement of SP by (1) determining the impact of muscle activation level and stimulus intensity (SI) on the duration of SP, and, (2) studying the relationship between motor evoked potential (MEP) and SP, using targeted stimulus delivery. Single magnetic pulses were focused on the optimal representation area of the thenar musculature on primary motor cortex. We utilized real-time 3D-positioning of TMS-evoked electric field on anatomical structures derived from individual MR-images. The SI varied from 80% to 120% of individual resting motor threshold (MT). Muscle activation levels varied from 20% to 80% of the maximal voluntary contraction (MVC). Contralateral SP lengthened significantly with increasing SI independent of target muscle activation. The peak amplitude of the MEP was affected by SI and force. Latency and duration of the MEP were practically unaffected by SI or force. Focal stimulation at 110-120% MT and approximately 50% MVC (with only negligible need for control) provides most stable and informative SP. MEP should be included in SP as the error from marking the onset diminishes. This study provides a guideline for the consistent measurement of SP, which is applicable when using navigated or traditional TMS.

Tolerance of pyramidal tract to gamma knife radiosurgery based on diffusion-tensor tractography.

PURPOSE: To minimize the morbidity of radiosurgery for critically located lesions, we integrated diffusion-tensor tractography into treatment planning for gamma-knife radiosurgery. We calculated the refined tolerance of the pyramidal tract (PT) after prospective application of the technique to additional patients. METHODS AND MATERIALS: The relationship between the dosimetry during treatment planning and the development of subsequent motor complications was investigated in 24 patients, 9 studied retrospectively and 15 studied prospectively. The maximal dose to the PT and the volumes of the PT that received > or = 20 Gy (20-Gy volume) and > or = 25 Gy (25-Gy volume) were calculated. Univariate logistic regression analyses were used to produce dose-response curves. Differences in the tolerable dose according to the PT location were calculated. RESULTS: Univariate logistic regression analysis of the motor complications revealed a significant independent correlation with the maximal dose to the PT and the 20- and 25-Gy volumes. The maximal dose to the PT with a 5% risk of motor complications was 23 Gy compared with 15 Gy in our previous report. The risk of motor complications was significantly greater in the internal capsule than in the corona radiata for the 20- and 25-Gy volumes in generalized Wilcoxon tests (p = 0.031), although no significant difference was observed for the maximal dose. CONCLUSION: The tolerable dose of the PT was greater than that previously reported. The internal capsule was more sensitive to high-dose irradiation over a wide area of the PT, probably owing to the dense concentration of motor fibers.

Informing dose-finding studies of repetitive transcranial magnetic stimulation to enhance motor function: a qualitative systematic review.

OBJECTIVE: Repetitive transcranial magnetic stimulation (rTMS) of the lesioned hemisphere might enhance motor recovery after stroke, but the appropriate dose (parameters of rTMS) remains uncertain. The present review collates evidence of the effect of rTMS on corticospinal pathway excitability and motor function in healthy adults and in people after stroke. METHODS: The authors searched MEDLINE and EMBASE (1996 to April 2007), their own collection of peer-reviewed articles, and the reference lists of included studies. They included healthy adults or people with stroke who received rTMS to the primary motor cortex to facilitate or inhibit contralateral corticospinal excitability or movement control. FINDINGS: Of the 625 references identified, 37 studies were included with 455 healthy adults (34 studies) and 69 people with stroke (3 studies). For healthy adults, the effects of rTMS on corticospinal pathway excitability varied within each frequency, for example, 1 Hz rTMS was found to facilitate, inhibit, and have no effect on amplitude of motor-evoked potentials (MEPs). After stroke there was a trend for recovery of MEPs (ie, presence of MEPs) after 10 daily sessions of 3 Hz rTMS (one study). Motor function in healthy adults might be adversely affected by 1 Hz rTMS (two studies), whereas combined frequency rTMS was found to have no effect (one study). INTERPRETATION: There is as yet insufficient published evidence to guide the dose of rTMS to the lesioned hemisphere after stroke to improve recovery of a paretic limb. Moreover, it is apparent that there is variability in response to rTMS in healthy adults. Dose-finding studies in groups of well-characterized stroke patients are needed.

Cortical and spinal modulation of antagonist coactivation during a submaximal fatiguing contraction in humans.

This study investigates the control mechanisms at the cortical and spinal levels of antagonist coactivation during a submaximal fatiguing contraction of the elbow flexors at 50% of maximal voluntary contraction (MVC). We recorded motor-evoked potentials in the biceps brachii and triceps brachii muscles in response to magnetic stimulation of the motor cortex (MEP) and corticospinal tract (cervicomedullary motor-evoked potentials--CMEPs), as well as the Hoffmann reflex (H-reflex) and maximal M-wave (Mmax) elicited by electrical stimulation of the brachial plexus, before, during, and after the fatigue task. The results showed that although the coactivation ratio did not change at task failure, the MVC torque produced by the elbow flexors declined by 48% (P < 0.01) with no change in MVC torque for the elbow extensors. While the MEP and CMEP areas (normalized to Mmax) of the biceps brachii increased ( approximately 50%) over the first 40% of the time to task failure and then plateaued, both responses in the triceps brachii increased ( approximately 150-180%) gradually throughout the fatigue task. In contrast to the monotonic increase in the MEP and CMEP of the antagonist muscles, the H-reflex of the triceps brachii exhibited a biphasic modulation, increasing during the first part of the contraction before declining subsequently to 65% of its initial value. Collectively, these results suggest that the level of coactivation during a fatiguing contraction is mediated by supraspinal rather than spinal mechanisms and involves differential control of agonist and antagonist muscles.

Effects of transcranial direct current stimulation on the excitability of the leg motor cortex.

Transcranial direct current stimulation (tDCS) of the human motor cortex at an intensity of 1 mA has been shown to be efficacious in increasing (via anodal tDCS) or decreasing (via cathodal tDCS) the excitability of corticospinal projections to muscles of the hand. In this study, we examined whether tDCS at currents of 2 mA could effect similar changes in the excitability of deeper cortical structures that innervate muscles of the lower leg. Similar to the hand area, 10 min of stimulation with the anode over the leg area of the motor cortex increased the excitability of corticospinal tract projections to the tibialis anterior (TA) muscle, as reflected by an increase in the amplitude of the motor evoked potentials (MEPs) evoked by transcranial magnetic stimulation. MEP amplitudes recorded at rest and during a background contraction were increased following anodal tDCS and remained elevated at 60 min compared to baseline values by 59 and 35%, respectively. However, in contrast to the hand, hyperpolarizing cathodal stimulation at equivalent currents had minimal effect on the amplitude of the MEPs recorded at rest or during background contraction of the TA muscle. These results suggest that it is more difficult to suppress the excitability of the leg motor cortex with cathodal tDCS than the hand area of the motor cortex.

Homeostatic plasticity in human motor cortex demonstrated by two consecutive sessions of paired associative stimulation.

Long-term potentiation (LTP) and long-term depression (LTD) underlie most models of learning and memory, but neural activity would grow or shrink in an uncontrolled manner, if not guarded by stabilizing mechanisms. The Bienenstock-Cooper-Munro (BCM) rule proposes a sliding threshold for LTP/LTD induction: LTP induction becomes more difficult if neural activity was high previously. Here we tested if this form of homeostatic plasticity applies to the human motor cortex (M1) in vivo by examining the interactions between two consecutive sessions of paired associative stimulation (PAS). PAS consisted of repeated pairs of electrical stimulation of the right median nerve followed by transcranial magnetic stimulation of the left M1. The first PAS session employed an interstimulus interval equalling the individual N20-latency of the median nerve somatosensory-evoked cortical potential plus 2 ms, N20-latency minus 5 ms, or a random alternation between these intervals, to induce an LTP-like increase in motor-evoked potential (MEP) amplitudes in the right abductor pollicis brevis muscle (PAS(LTP)), an LTD-like decrease (PAS(LTD)), or no change (PAS(Control)), respectively. The second PAS session 30 min later was always PAS(LTP). It induced an moderate LTP-like effect if conditioned by PAS(Control), which increased if conditioned by PAS(LTD), but decreased if conditioned by PAS(LTP). Effects on MEP amplitude induced by the second PAS session exhibited a negative linear correlation with those in the first PAS session. Because the two PAS sessions activate identical neuronal circuits, we conclude that 'homosynaptic-like' homeostatic mechanisms in accord with the BCM rule contribute to regulating plasticity in human M1.

Suppression of LTP-like plasticity in human motor cortex by the GABAB receptor agonist baclofen.

Previous experiments in slice preparations revealed that pharmacological activation of GABAB receptors down- or up-regulates long-term potentiation (LTP), depending on whether increase of GABAB receptor mediated inhibitory postsynaptic potentials or decrease of presynaptic auto-inhibition of GABAA receptor mediated inhibition predominates. The effects of GABAB receptor activation on LTP in humans in vivo are unknown. Here we show, by using transcranial magnetic stimulation, that the GABAB receptor agonist baclofen decreases paired associative stimulation induced LTP-like plasticity in human motor cortex. This suggests that increased GABAB mediated inhibitory postsynaptic potentials drive this effect, and that baclofen may have a negative impact on LTP-dependent behavioural processes such as motor learning.