ABSTRACT
BACKGROUND: Cognitive impairment is a common medical issue in rat sarcoma (RAS) pathway disorders, so-called RASopathies, like Neurofibromatosis type 1 (NF1) or Noonan syndrome (NS). It is presumed to be caused by impaired synaptic plasticity. In animal studies, pathway-specific pharmacological interventions with lovastatin (LOV) and lamotrigine (LTG) have been shown to improve synaptic plasticity as well as cognitive function. The aim of this clinical trial is to translate the findings of animal studies to humans and to probe the effect of lovastatin (NS) and lamotrigine (NS and NF1) on synaptic plasticity and cognitive function/alertness in RASopathies. METHODS: Within this phase IIa, monocentre, randomized, double-blind, parallel-group, placebo-controlled, cross-over clinical trial (syn. SynCoRAS), three approaches (approaches I-III) will be carried out. In patients with NS, the effect of LTG (approach I) and of LOV (approach II) is investigated on synaptic plasticity and alertness. LTG is tested in patients with NF1 (approach III). Trial participants receive a single dose of 300 mg LTG or placebo (I and III) and 200 mg LOV or placebo (II) daily for 4 days with a cross-over after at least 7 days. Synaptic plasticity is investigated using a repetitive high-frequency transcranial magnetic stimulation (TMS) protocol called quadri-pulse theta burst stimulation (qTBS). Attention is examined by using the test of attentional performance (TAP). Twenty-eight patients are randomized in groups NS and NF1 with n = 24 intended to reach the primary endpoint (change in synaptic plasticity). Secondary endpoints are attention (TAP) and differences in short interval cortical inhibition (SICI) between placebo and trial medication (LTG and LOV). DISCUSSION: The study is targeting impairments in synaptic plasticity and cognitive impairment, one of the main health problems of patients with RASopathies. Recent first results with LOV in patients with NF1 have shown an improvement in synaptic plasticity and cognition. Within this clinical trial, it is investigated if these findings can be transferred to patients with NS. LTG is most likely a more effective and promising substance improving synaptic plasticity and, consecutively, cognitive function. It is expected that both substances are improving synaptic plasticity as well as alertness. Changes in alertness may be a precondition for improvement of cognition. TRIAL REGISTRATION: The clinical trial is registered in ClinicalTrials.gov (NCT03504501; https://www. CLINICALTRIALS: gov ; date of registration: 04/11/2018) and in EudraCT (number 2016-005022-10).
Subject(s)
Cognition , Neuronal Plasticity , Humans , Lamotrigine , Double-Blind Method , Anticonvulsants/therapeutic use , Lovastatin/therapeutic useABSTRACT
Coordinated bimanual control depends on information processing in different intra- and interhemispheric networks that differ with respect to task symmetry and laterality of execution. Aging and age-related cognitive impairments, but also sex can have detrimental effects on connectivity of these networks. We therefore expected effects of age, cognitive function and sex on bimanual force coordination. We furthermore expected these effects to depend on the characteristics of the task (i.e., difficulty and symmetry). 162 right handed participants (19 younger adults [YA], 21-30 years, 9 females; 52 cognitively healthy older adults [HOA], 80-91 years, 32 females; and 91 older adults with mild cognitive impairments [MCI] 80-91 years, 37 females) performed isometric bimanual force control tasks that required following constant or alternating (cyclic sine-wave) targets and varied in symmetry, i.e., (i) constant symmetric, asymmetric [with constant left and alternating right (ii) or vice versa (iii)], (iv) alternating in- and (v) alternating antiphase (both hands alternating with 0° or 180° relative phase, respectively). We analyzed general performance (time on target), bimanual coordination as coupling between hands (linear correlation coefficient) and structure of variability (i.e., complexity measured through detrended fluctuation analysis). Performance and coupling strongly depended on task symmetry and executing hand, with better performance in symmetric tasks and in asymmetric tasks when the left hand produced a constant and the right hand an alternating force. HOA and MCI, compared to YA, showed poorer performance (time on target) and reduced coupling in in- and antiphase tasks. Furthermore, both groups of OA displayed less complex structure in alternating force production tasks, a marker of reduced control. In addition, we found strong sex effects with females displaying reduced coupling during in- and antiphase coordination and less complex variably structure in constant force production. Results of this study revealed strong effects of age, but also sex on bimanual force control. Effects depended strongly on task symmetry and executing hand, possibly due to different requirements in interhemispheric information processing. So far, we found no clear relationship between behavioral markers of bimanual force control and age-related cognitive decline (compared to healthy aging), making further investigation necessary.
ABSTRACT
Studying brain mechanisms underlying the prediction of observed action, the dorsal premotor cortex (PMd) has been suggested a key area. The present study probed this notion using repetitive transcranial magnetic stimulation (rTMS) to test whether interference in this area would affect the accuracy in predicting the time course of object directed actions performed with the right hand. Young and healthy participants observed actions in short videos. These were briefly occluded from view for 600 ms and resumed immediately afterwards. The task was to continue the action mentally and to indicate after each occlusion, whether the action was resumed at the right moment (condition in-time) or shifted. In a first run, single-pulse transcranial magnetic stimulation (sTMS) was delivered over the left primary hand-area during occlusion. In the second run, rTMS over the left PMd was applied during occlusion in half of the participants [experimental group (EG)]. The control group (CG) received sham-rTMS over the same area. Under rTMS, the EG predicted less trials correctly than in the sTMS run. Sham-rTMS in the CG had no effects on prediction. The interference in PMd interacted with the type of manipulation applied to the action's time course occasionally during occlusion. The performance decrease of the EG was most pronounced in conditions in which the continuations after occlusions were too late in the action's course. The present results extend earlier findings suggesting that real-time action prediction requires the integrity of the PMd. Different functional roles of this area are discussed. Alternative interpretations consider either simulation of specific motor programming functions or the involvement of a feature-unspecific predictor.
