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Neuronal plasticity is considered to be the neurophysiological correlate of learning and memory and changes in corticospinal excitability play a key role in the normal development of the central nervous system as well as in developmental disorders. In a previous study, it was shown that quadri-pulse theta burst stimulation (qTBS) can induce bidirectional changes in corticospinal excitability (1). There, a quadruple burst consisted of four single-sine-wave (SSW) pulses with a duration of 160 μs and inter-pulse intervals of 1.5 ms to match I-wave periodicity (666 Hz). In the present study, the pulse shape was modified applying double-sine-waves (DSW) rather than SSW pulses, while keeping the pulse duration at 160 μs. In two separate sessions, we reversed the current direction of the DSW pulse, so that its second component elicited either a mainly posterior-to-anterior (DSW PA-qTBS) or anterior-to-posterior (DSW AP-qTBS) directed current in the precentral gyrus. The after-effects of DSW qTBS on corticospinal excitability were examined in healthy individuals (n = 10) with single SSW TMS pulses. For single-pulse SSW TMS, the second component produced the same preferential current direction as DSW qTBS but had a suprathreshold intensity, thus eliciting motor evoked potentials (PA-MEP or AP-MEP). Single-pulse SSW TMS revealed bidirectional changes in corticospinal excitability after DSW qTBS, which depended on the preferentially induced current direction. DSW PA-qTBS at 666 Hz caused a stable increase in PA-MEP, whereas AP-qTBS at 666 Hz induced a transient decrease in AP-MEP. The sign of excitability following DSW qTBS at I-wave periodicity was opposite to the bidirectional changes after SSW qTBS. The results show that the pulse configuration and induced current direction determine the plasticity-effects of ultra-high frequency SSW and DSW qTBS at I-wave periodicity. These findings may offer new opportunities for short non-invasive brain stimulation protocols that are especially suited for stimulation in children and patients with neurological or neurodevelopmental disorders.

Synaptic plasticity in the form of long-term potentiation (LTP) and long-term depression (LTD) is considered to be the neurophysiological correlate of learning and memory. Impairments are discussed to be one of the underlying pathophysiological mechanisms of developmental disorders. In so-called RASopathies [e.g., neurofibromatosis 1 (NF1)], neurocognitive impairments are frequent and are affected by components of the RAS pathway which lead to impairments in synaptic plasticity. Transcranial magnetic stimulation (TMS) provides a non-invasive method to investigate synaptic plasticity in humans. Here, we review studies using TMS to evaluate synaptic plasticity in patients with RASopathies. Patients with NF1 and Noonan syndrome (NS) showed reduced cortical LTP-like synaptic plasticity. In contrast, increased LTP-like synaptic plasticity has been shown in Costello syndrome. Notably, lovastatin normalized impaired LTP-like plasticity and increased intracortical inhibition in patients with NF1. TMS has been shown to be a safe and efficient method to investigate synaptic plasticity and intracortical inhibition in patients with RASopathies. Deeper insights in impairments of synaptic plasticity in RASopathies could help to develop new options for the therapy of learning deficits in these patients.

Aim We aimed to investigate the induction of long-term potentiation (LTP)-like plasticity by paired associative stimulation (PAS) in patients with high-functioning autism and Asperger syndrome (HFA/AS). Method PAS with an interstimulus interval between electrical and transcranial magnetic stimulation of 25 ms (PAS25) was performed in patients with HFA/AS (n=9; eight males, one female; mean age 17y 11mo, SD 4y 5mo) and in typically developing age-matched volunteers (n=9; five males, four females; mean age 22y 4mo, SD 5y 2mo). The amplitude of motor-evoked potentials was measured before PAS25, immediately after stimulation, and 30 minutes and 60 minutes later. A PAS protocol adapted to individual N20 latency (PASN20+2) was performed in six additional patients with HFA/AS. Short-interval intracortical inhibition was measured using paired-pulse stimulation. Results In contrast to the typically developing participants, the patients with HFA/AS did not show a significant increase in motor-evoked potentials after PAS25. This finding could also be demonstrated after adaptation for N20 latency. Short-interval intracortical inhibition of patients with HFA/AS was normal compared with the comparison group and did not correlate with PAS effect. Interpretation Our results show a significant impairment of LTP-like plasticity induced by PAS in individuals with HFA/AS compared with typically developing participants. This finding is in accordance with results from animal studies as well as human studies. Impaired LTP-like plasticity in patients with HFA/AS points towards reduced excitatory synaptic connectivity and deficits in sensory-motor integration in these patients.

Background Motor learning takes place in several phases. Animal experiments suggest that synaptic plasticity plays an important role in acquisition of motor skills, whereas retention of motor performance is most likely achieved by other mechanisms. Objective/hypothesis This study compared two spacing approaches and investigated the time course of synaptic plasticity after spaced motor practice (MP). Methods Twenty subjects performed a ballistic thumb flexion task in sessions of 6 × 10 minutes or 12 × 5 minutes. We measured peak acceleration of the target movement throughout the experiment and cortical excitability more than 60 minutes after MP via transcranial magnetic stimulation (TMS). After a retention period, both parameters were re-evaluated. Results Mean peak acceleration of the target movement significantly increased (6 × 10 minutes: 21.61 m/s 2 versus 30.80 m/s 2 , P = .002; 12 × 5 minutes: 18.52 m/s 2 versus 29.65 m/s 2 , P = .01). In both training groups, motor evoked potential (MEP) amplitudes of the trained muscle continuously increased after MP (6 × 10 min: 0.93 mV versus 1.57 mV, P = .19; 12 × 5 min: 0.90 mV versus 1.76 mV, P = .004). After the retention period, motor performance was still significantly enhanced, whereas MEP amplitudes were no longer significantly increased. Conclusions These findings do not provide evidence that in small scale motor learning the duration of practice and rest influences behavioral improvement or induction of cortical plasticity. Our study demonstrates that cortical plasticity after MP displays a dynamical time course that might be caused by different mechanisms.

Question Changes in synaptic and neuronal efficacy such as long-term potentiation (LTP) and long-term depression (LTD) are thought to reflect synaptic processes underlying learning and memory. Homeostatic plasticity is considered to stabilize neural activity within a physiologically reasonable and dynamic range. Quadri-pulse-thetaburst stimulation (qTBS) is a recently introduced patterned transcranial magnetic stimulation (TMS) protocol that induced lasting increase or decrease in neuronal excitability of human primary motor cortex (M1) probably corresponding to the model of LTP- and LTD-like plasticity. Here, we aimed to probe homeostatic and metaplastic interactions of an inhibitory priming qTBS protocol on subsequent facilitating and inhibitory qTBS. Methods We investigated the priming mechanisms of inhibitory qTBS on subsequent facilitating qTBS (experiment 1) in 8 healthy volunteers and on subsequent inhibitory qTBS (experiment 2) in 9 healthy volunteers. Inhibitory qTBS consisted of 360 bursts given continuously to M1 (i.e. 1440 full-sine pulses) with bursts of four biphasic TMS pulses (duration 160 μ s) separated by inter-stimulus intervals (ISI) of 50 ms (20 Hz) and inter-burst intervals of 200 ms (5 Hz) (qTBS50/200). Facilitatory qTBS consisted of the same burst pattern but with ISI of 5 ms (200 Hz) (qTBS5/200). TMS was applied by a custom-made magnet stimulator (MSB, Munich). Resting motor threshold (RMT) and motor evoked potential (MEP) amplitudes with stimulus intensities to target amplitudes of 1 mV were measured before priming qTBS50/200 (pre), directly after priming qTBS50/200 (post1), after 15 min (post2) and after 30 min (post3). Following post 3 measurements, the second stimulation (qTBS5/200 or qTBS50/200) was applied and the RMT and MEP were measured for 60 min (post4–post7). Results In experiment 1 (qTBS50/200–qTBS5/200), priming with qTBS50/200 led to a decrease of MEP amplitudes (post1–3), while MEP amplitudes increased following subsequent qTBS5/200 (post 4–7). Mean changes of post 4–7 increased significantly as compared to mean changes of post 1–3. In experiment 2 (qTBS50/200–qTBS50/200), MEP amplitudes decreased following the priming protocol (post 1–3) and returned to baseline with a slight increase on post 6 after the subsequent qTBS50/200 protocol. Mean changes of post 4–7 increased significantly as compared to mean changes of post 1–3. Conclusion Our preliminary results may point towards homeostatic mechanisms of facilitatory qTBS5/200 following priming with qTBS50/200. In contrast, subsequent qTBS50/200 led to a de-depression like effect of MEP amplitudes suggesting metaplastic effects of two inhibitory qTBS protocols applied over M1. Our findings may support the assumption that changes in cortico-spinal excitability following qTBS represent LTP- and LTD-like changes in synaptic transmission and corroborate metaplastic de-depression effects of high-frequency patterned rTMS protocols in human M1.

Patterned transcranial magnetic stimulation (TMS) such as theta burst stimulation (TBS) or quadri-pulse stimulation (QPS) can induce changes in cortico-spinal excitability, commonly referred to as long-term potentiation (LTP)-like and long-term depression (LTD)-like effects in human motor cortex (M1). Here, we aimed to test the plasticity-inducing capabilities of a novel protocol that merged TBS and QPS. 360 bursts of quadri-pulse TBS (qTBS) were continuously given to M1 at 90% of active motor threshold (1440 full-sine pulses). In a first experiment, stimulation frequency of each burst was set to 666 Hz to mimic the rhythmicity of the descending cortico-spinal volleys that are elicited by TMS (i.e., I-wave periodicity). In a second experiment, burst frequency was set to 200 Hz to maximize postsynaptic Ca2+ influx using a temporal pattern unrelated to I-wave periodicity. The second phase of sinusoidal TMS pulses elicited either a posterior-anterior (PA) or anterior-posterior (AP) directed current in M1. Motor evoked potentials (MEPs) were recorded before and after qTBS to probe changes in cortico-spinal excitability. PA-qTBS at 666 Hz caused a decrease in PA-MEP amplitudes, whereas AP-qTBS at 666 Hz induced an increase in mean AP-MEP amplitudes. At a burst frequency of 200 Hz, PA-qTBS and AP-qTBS produced an increase in cortico-spinal excitability outlasting for at least 60 minutes in PA- and AP-MEP amplitudes, respectively. Continuous qTBS at 666 Hz or 200 Hz can induce lasting changes in cortico-spinal excitability. Induced current direction in the brain appears to be relevant when qTBS targets I-wave periodicity, corroborating that high-fidelity spike timing mechanisms are critical for inducing bi-directional plasticity in human M1.

Aim Early unilateral brain lesions can lead to a persistence of ipsilateral corticospinal projections from the contralesional hemisphere, which can enable the contralesional hemisphere to exert motor control over the paretic hand. In contrast to the primary motor representation (M1), the primary somatosensory representation (S1) of the paretic hand always remains in the lesioned hemisphere. Here, we report on differences in exercise-induced neuroplasticity between individuals with such ipsilateral motor projections (ipsi) and individuals with early unilateral lesions but ‘healthy’ contralateral motor projections (contra). Method Sixteen children and young adults with congenital hemiparesis participated in the study (contralateral [Contra] group: n=7, four females, three males; age range 10–30y, median age 16y; ipsilateral [Ipsi] group: n=9, four females, five males; age range 11–31y, median age 12y; Manual Ability Classification System levels I to II in all individuals in both groups). The participants underwent a 12-day intervention of constraint-induced movement therapy (CIMT), consisting of individual training (2h/d) and group training (8h/d). Before and after CIMT, hand function was tested using the Wolf Motor Function Test (WMFT) and diverging neuroplastic effects were observed by transcranial magnetic stimulation (TMS), functional magnetic resonance imaging (fMRI), and magnetoencephalography (MEG). Statistical analysis of TMS data was performed using the non-parametric Wilcoxon signed-rank test for pair-wise comparison; for fMRI standard statistical parametric and non-parametric mapping (SPM5, SnPM3) procedures (first level/second level) were carried out. Statistical analyses of MEG data involved analyses of variance (ANOVA) and t-tests. Results While MEG demonstrated a significant increase in S1 activation in both groups (p=0.012), TMS showed a decrease in M1 excitability in the Ipsi group (p=0.036), but an increase in M1 excitability in the Contra group (p=0.043). Similarly, fMRI showed a decrease in M1 activation in the Ipsi group, but an increase in activation in the M1–S1 region in the Contra group (for both groups p

Background Transcranial magnetic stimulation (TMS) of the human primary motor hand area (M1-HAND) can produce multiple descending volleys in fast-conducting corticospinal neurons, especially so-called indirect waves (I-waves) resulting from trans-synaptic excitation. Facilitatory interaction between these I-waves can be studied non-invasively using a paired-pulse paradigm referred to as short-interval intracortical facilitation (SICF). Objective/hypothesis We examined whether SICF depends on waveform and current direction of the TMS pulses. Methods In young healthy volunteers, we applied single- and paired-pulse TMS to M1-HAND. We probed SICF by pairs of monophasic or half-sine pulses at suprathreshold stimulation intensity and inter-stimulus intervals (ISIs) between 1.0 and 5.0 ms. For monophasic paired-pulse stimulation, both pulses had either a posterior–anterior (PA) or anterior–posterior (AP) current direction (AP–AP or PA–PA), whereas current direction was reversed between first and second pulse for half-sine paired-pulse stimulation (PA–AP and AP–PA). Results Monophasic AP–AP stimulation resulted in stronger early SICF at 1.4 ms relative to late SICF at 2.8 and 4.4 ms, whereas monophasic PA–PA stimulation produced SICF of comparable size at all three peaks. With half-sine stimulation the third SICF peak was reduced for PA–AP current orientation compared with AP–PA. Conclusion SICF elicited using monophasic as well as half-sine pulses is affected by current direction at clearly suprathreshold intensities. The impact of current orientation is stronger for monophasic compared with half-sine pulses. The direction-specific effect of paired-pulse TMS on the strength of early versus late SICF shows that different cortical circuits mediate early and late SICF.

Objective Noonan syndrome (NS; OMIM 163950 ) is a developmental disorder caused by activating mutations in various components of the RAS-MAPK pathway. Recent in vitro studies demonstrated impairment of synaptic plasticity caused by RAS-MAPK pathway hyperactivity. Induction of synaptic plasticity critically depends on the level of attention. We therefore studied the induction of synaptic plasticity in patients with NS and healthy volunteers under different conditions of attention using transcranial magnetic stimulation. Methods We investigated 10 patients with NS and healthy controls (HC) using paired associative stimulation (PAS) with different attention levels (unspecific, visual and electrical attention control). Changes in motor evoked potential (MEP) amplitudes were assessed immediately after as well as 30 and 60 min after PAS. Results We demonstrated that MEP amplitudes of healthy controls significantly increased from 1.00 ± 0.17 to 1.74 ± 0.50 mV (p = 0.001), which was not seen in patients with Noonan-Syndrome (0.88 ± 0.09 to 1.10 ± 0.48 mV, p = 0.148) and there was a significant difference between both groups (p = 0.003) when using an unspecific attention control. Under specific electrical attention control, MEP amplitudes decreased significantly in patients with NS, whereas a visual attention focus diminished synaptic plasticity in healthy controls. Conclusion Our study provides evidence that synaptic plasticity is impaired in patients with NS, which is probably a consequence of constitutive activity of the RAS-MAPK pathway. The induction of synaptic plasticity in these patients critically depends on attention. Significance This is the first study that indicates reduced synaptic plasticity in patients with a RAS-pathway disorder. Our results may have direct implications for learning and memory strategies in patients with a RAS-pathway disorder.

Background: Transcranial magnetic stimulation (TMS) commonly uses so-called monophasic pulses where the initial rapidly changing current flow is followed by a critically dampened return current. It has been shown that a monophasic TMS pulse preferentially excites different cortical circuits in the human motor hand area (M1-HAND), if the induced tissue current has a posterior-to-anterior (PA) or anterior-to-posterior (AP) direction. Here we tested whether similar direction-specific effects could be elicited in M1-HAND using TMS pulses with a half-sine wave configuration. Results: In 10 young participants, we applied half-sine pulses to the right M1-HAND which elicited PA or AP currents with respect to the orientation of the central sulcus. Measurements of the motor evoked potential (MEP) revealed that PA half-sine stimulation resulted in lower resting motor threshold (RMT) than AP stimulation. When stimulus intensity (SI) was gradually increased as percentage of maximal stimulator output, the stimulus–response curve (SRC) of MEP amplitude showed a leftward shift for PA as opposed to AP half-sine stimulation. Further, MEP latencies were approximately 1 ms shorter for PA relative to AP half-sine stimulation across the entire SI range tested. When adjusting SI to the respective RMT of PA and AP stimulation, the direction-specific differences in MEP latencies persisted, while the gain function of MEP amplitudes was comparable for PA and AP stimulation. Conclusions: Using half-sine pulse configuration, single-pulse TMS elicits consistent direction-specific effects in M1-HAND that are similar to TMS with monophasic pulses. The longer MEP latency for AP half-sine stimulation suggests that PA and AP half-sine stimulation preferentially activates different sets of cortical neurons that are involved in the generation of different corticospinal descending volleys. Keywords: Transcranial magnetic stimulation, Current direction, Half-sine stimulus, I-waves, Stimulus–response curves, Motor cortex * Correspondence: volker.mall@tum.de †Equal contributors 1Department of Pediatrics, Technical University Munich, Kinderzentrum München gemeinnützige GmbH, Heiglhofstrasse 63, Munich 81377, Germany 2Department of Paediatrics and Adolescent Medicine, Division of Neuropaediatrics and Muscular Disorders, University Medical Centre Freiburg, Mathildenstr 1, Freiburg 79106, Germany Full list of author information is available at the end of the article © 2012 peerReviewed

Objective: Succinic semialdehyde dehydrogenase (SSADH) deficiency is a rare autosomal recessive disorder of GABA degradation leading to elevations in brain GABA and γ-hydroxybutyric acid (GHB). The effect of chronically elevated GABA and GHB on cortical excitability is unknown. We hypothesized that use-dependent downregulation of GABA receptor expression would promote cortical disinhibition rather than inhibition, predominantly via presynaptic GABAergic mechanisms. Methods: We quantified the magnitude of excitation and inhibition in primary motor cortex (M1) in patients with SSADH deficiency, their parents (obligate heterozygotes), age-matched healthy young controls, and healthy adults using single and paired pulse transcranial magnetic stimulation (TMS). Results: Long interval intracortical inhibition was significantly reduced and the cortical silent period was significantly shortened in patients with SSADH deficiency compared to heterozygous parents and control groups. Conclusions: Since long interval intracortical inhibition and cortical silent period are thought to reflect GABAB receptor–mediated inhibitory circuits, our results point to a particularly GABAB-ergic motor cortex dysfunction in patients with SSADH deficiency. This human phenotype is consistent with the proposed mechanism of use-dependent downregulation of postsynaptic GABAB receptors in SSADH deficiency animal models. Additionally, the results suggest autoinhibition of GABAergic neurons. This first demonstration of altered GABAB-ergic function in patients with SSADH deficiency may help to explain clinical features of the disease, and suggest pathophysiologic mechanisms in other neurotransmitter-related disorders. Neurology® 2012;79:47–54

Background Neuronal plasticity is the physiological correlate of learning and memory. In animal experiments, synaptic (i.e. long-term potentiation (LTP) and depression (LTD)) and intrinsic plasticity are distinguished. In human motor cortex, cortical plasticity can be demonstrated using transcranial magnetic stimulation (TMS). Changes in motor-evoked potential (MEP) amplitudes most likely represent synaptic plasticity and are thus termed LTP-like and LTD-like plasticity. Objective/hypothesis We investigated the role of changes of motor threshold and their relation to changes of MEP amplitudes. Methods We induced plasticity by paired associative stimulation (PAS) with 25 ms or 10 ms inter-stimulus interval or by motor practice (MP) in 64 healthy subjects aged 18–31 years (median 24.0). Results We observed changes of MEP amplitudes and motor threshold after PAS[25], PAS[10] and MP. In all three protocols, long-term individual changes in MEP amplitude were inversely correlated to changes in motor threshold (PAS[25]: P = .003, n = 36; PAS[10]: P = .038, n = 19; MP: P = .041, n = 19). Conclusion We conclude that changes of MEP amplitudes and MT represent two indices of motor cortex plasticity. Whereas increases and decreases in MEP amplitude are assumed to represent LTP-like or LTD-like synaptic plasticity of motor cortex output neurons, changes of MT may be considered as a correlate of intrinsic plasticity.

Introduction: It has been shown from invasive epidural recordings that in transcranial magnetic stimulation (TMS) a current in the brain flowing from a posterior to an anterior (p.a.) direction mainly evokes I1, I2 and I3 waves whereas a current flowing from an anterior to a posterior direction mainly evokes I3 waves. This leads to the hypotheses that in p.a. current direction the motor threshold (MT) is lower, motor evoked potentials (MEPs) are higher and latency is shorter than in a.p. direction. The aim of this study was to re-evaluate the inconsistent results in literature by means of a stimulation technique that enabled us to change the current direction without turning the coil. Methods: We investigated n=23 healthy subjects (female: n=12; mean age: 26.2±1.9 years). We recorded the MT, MEP amplitude to target 400µV (SI400µV), MT adapted IO curves and maximum stimulator output (MSO) adapted IO curves in a.p. and p.a. current direction (monophasic waveform) with the P-Stim 160 stimulator (Mag and More, Germany). Results: MT was significantly lower (p=0.003), MEP amplitudes (SI400µV) were significantly higher (p

Background One major attribute of transcranial magnetic stimulation (TMS) is the variability of motor-evoked potential (MEP) amplitudes, to which variations of coil positioning may contribute. Navigated TMS allows the investigator to retrieve a stimulation site with an accuracy of 2.5 mm and to retain coil position with low spatial divergence during stimulation. Objective The purpose of this study was to investigate whether increased spatial constancy of the coil using a navigational system decreases the variability of MEP amplitudes and increases their reproducibility between different points in time of investigation. Methods We investigated eight healthy subjects (mean age 23.8 ± 1.2 years, range 22-25, four women, four men) at three different points in time with and without an optically tracked frameless navigational device, respectively. Input-output curves, motor threshold, and MEP amplitudes were recorded. We calculated the coefficient of variation as statistical parameter of variability. Reproducibility between different sessions was assessed via the MEP amplitude. Results The coefficient of variance of MEP amplitudes did not show a distinct difference between navigated and non-navigated TMS in input-output curves. MEP amplitudes, indicating reproducibility, did not significantly differ between sessions with and without navigated TMS, either. Conclusions Our results do not support the hypothesis that increased spatial constancy using a navigational system improves variability and reproducibility of MEP amplitudes. Variability of MEPs might mainly be due to not influenceable neurophysiologic factors such as undulant cortical excitability and spinal desynchronization.

Objective Low-frequency stimulation, which does not induce long-term potentiation (LTP) or long-term potentiation (LTD) by itself, suppresses consecutive LTP or LTD induction in vitro. We tested whether a similar interaction occurs in the human motor cortex. Methods LTP- or LTD-like plasticity was induced using paired associative stimulation (PAS) with 25 and 10 ms interstimulus interval and conditioned by suprathreshold repetitive transcranial magnetic stimulation (rTMS) at a frequency of 0.1 Hz. Results RTMS completely abolished the significant increase of motor-evoked potential (MEP) amplitudes after PAS25ms (PAS25ms only: 1.05 ± 0.14 to 1.76 ± 0.66 mV, p = 0.001; rTMS + PAS25ms: 1.08 ± 0.18 to 1.02 ± 0.44 mV, n.s.) and also abolished the significant decrease of MEP amplitudes after PAS10ms (PAS10ms only: 1.00 ± 0.14 to 0.73 ± 0.32 mV; rTMS + PAS10ms: 1.15 ± 0.35 to 1.25 ± 0.43 mV, p = 0.006). RTMS alone did not significantly alter MEP amplitudes but increased SICI and LICI. Conclusions Low frequency stimulation increases intracortical inhibition and occludes LTP- and LTD-like plasticity in the human motor cortex. Significance This finding supports the concept that metaplasticity in the human motor cortex follows similar rules as metaplasticity in in vitro experiments.

Background Neurofibromatosis type 1 (NF1) is one of the most common genetic disorders causing learning disabilities by mutations in the neurofibromin gene, an important inhibitor of the RAS pathway. In a mouse model of NF1, a loss of function mutation of the neurofibromin gene resulted in increased gamma aminobutyric acid (GABA)-mediated inhibition which led to decreased synaptic plasticity and deficits in attentional performance. Most importantly, these defictis were normalized by lovastatin. This placebo-controlled, double blind, randomized study aimed to investigate synaptic plasticity and cognition in humans with NF1 and tried to answer the question whether potential deficits may be rescued by lovastatin. Methods In NF1 patients (n = 11; 19–44 years) and healthy controls (HC; n = 11; 19–31 years) paired pulse transcranial magnetic stimulation (TMS) was used to study intracortical inhibition (paired pulse) and synaptic plasticity (paired associative stimulation). On behavioural level the Test of Attentional Performance (TAP) was used. To study the effect of 200 mg lovastatin for 4 days on all these parameters, a placebo-controlled, double blind, randomized trial was performed. Results In patients with NF1, lovastatin revealed significant decrease of intracortical inhibition, significant increase of synaptic plasticity as well as significant increase of phasic alertness. Compared to HC, patients with NF1 exposed increased intracortical inhibition, impaired synaptic plasticity and deficits in phasic alertness. Conclusions This study demonstrates, for the first time, a link between a pathological RAS pathway activity, intracortical inhibition and impaired synaptic plasticity and its rescue by lovastatin in humans. Our findings revealed mechanisms of attention disorders in humans with NF1 and support the idea of a potential clinical benefit of lovastatin as a therapeutic option.