The present behavioral findings in NF

The present behavioral findings in NF1 patients were characterized by a decline of skill acquisition compared to controls, driven by two factors: (1) a prostaglandin f2 alpha in fast-online learning, but also (2) by a prominent decrement in offline improvements between training sessions. The manifestation of NF1-related GABAergic dysfunctions in the inhibitory motor cortical system might be one mechanism involved in the present deficits. Even though intracortical inhibition is mainly associated with the early acquisition phase, it is likely the neural processes leading to successful consolidation start to operate during practice and evolve in the time after training. Support to this concept comes from the finding that facilitatory anodal tDCS, an intervention known to decrease GABAergic neurotransmission in the M1 (Stagg et al., 2009), applied concurrently with training, can enhance offline learning in healthy subjects (Reis et al., 2009). The NF1 patients included in the present study were carefully selected to make sure that all of them were clinically asymptomatic, with a normal IQ and neuropsychological testing, and well integrated in daily life. Even then the patients showed clear deficits compared to healthy controls within the present complex motor skill acquisition paradigm. As the underlying mechanisms of the disease are apparent since birth, one can speculate that they have well adapted to their deficits in skill acquisition on a behavioral level, relevant in daily life. A similar pattern, present in the controlled environment of this study, is a reduced fast-online learning in the patients. While overall online learning over the five training days was not different from controls, indicating a distinct time course of online learning in these patients. Nevertheless, they still showed a reduction in offline learning leading to an overall difference in the magnitude of skill acquisition. This impairment seen in a complex motor task did not prevent the patients from being integrated into normal professional and private lives. Rather, the patients may have had to adapt for these deficits, e.g., through longer periods of practice to acquiring skills, a question that has to be addressed in upcoming studies. Strikingly, some of these patients reported that cerebral cortex might have had slight delays in motoric development and have received physio- or occupational therapy during childhood (Table 2). A recent study by Omrani et al. (2015) suggests an alternative mechanism of inhibition in a mouse model: a weakening of hyperpolarization-activated cyclic nucleotide-gated (HCN) current might be the cause for increased inhibition in NF1 patients. The present results are subject to some limitations. Although matched for age and educational level, no detailed neuropsychological examination and scales or motor development questionnaires were acquired for the control group. Offline learning effects are also related to sleep-dependent consolidation processes, as reported within explicit motor sequence learning paradigms (Walker et al., 2002). Despite the fact that there were no differences in sleep questionnaires between both groups, we cannot rule out an influence in alterations of sleep parameters (such as the architecture) in NF1 patients, as suggested in children with NF1 (Licis et al., 2013). It is of note that although there is evidence for cognitive and attentional deficits in NF1 children, the sample of patients who participated in the present study were carefully selected and did not show impairments in cognitive or attentional abilities to avoid potential confounders (e.g. attention deficit disorder or cognitive impairment). Lastly, a factor limiting interpretation of the results might be the small sample size of the study, due to the highly selective nature of the patient group to remove confounding factors.
Author Contributions
Acknowledgements This work has been supported by the German Research Foundation (DFG), SFB 936 „Multi-Site Communication in the Brain“, project C4 to F.C.H. and by the Bundesverband Neurofibromatose. The funders did not have any role in study design, data collection, data analysis, interpretation, writing of the report.