title: Impairment of Procedural Learning and Motor Intracortical Inhibition in Neurofibromatosis Type 1 Patients.
abstract: BACKGROUND
  Cognitive difficulties are the most common neurological complications in neurofibromatosis type 1 (NF1) patients. Recent animal models proposed increased GABA-mediated inhibition as one underlying mechanism directly affecting the induction of long-term potentiation (LTP) and learning. In most adult NF1 patients, apparent cognitive and attentional deficits, tumors affecting the nervous system and other confounding factors for neuroscientific studies are difficult to control for. Here we used a highly specific group of adult NF1 patients without cognitive or nervous system impairments. Such selected NF1 patients allowed us to address the following open questions: Is the learning process of acquiring a challenging motor skill impaired in NF1 patients? And is such an impairment in relation to differences in intracortical inhibition?
  
  
  METHODS
  We used an established non-invasive, double-pulse transcranial magnetic stimulation (dp-TMS) paradigm to assess practice-related modulation of intracortical inhibition, possibly mediated by gamma-minobutyric acid (GABA)ergic-neurotransmission. This was done during an extended learning paradigm in a group of NF1 patients without any neuropsychological deficits, functioning normally in daily life and compared them to healthy age-matched controls.
  
  
  RESULTS
  NF1 patients experienced substantial decline in motor skill acquisition (F = 9.2, p = 0.008) over five-consecutives training days mediated through a selective reduction in the early acquisition (online) and the consolidation (offline) phase. Furthermore, there was a consistent decrease in task-related intracortical inhibition as a function of the magnitude of learning (T = 2.8, p = 0.014), especially evident after the early acquisition phase.
  
  
  CONCLUSIONS
  Collectively, the present results provide evidence that learning of a motor skill is impaired even in clinically intact NF1 patients based, at least partially, on a GABAergic-cortical dysfunctioning as suggested in previous animal work.
authors.affiliation: Brain Imaging and NeuroStimulation (BINS) Laboratory, Department of Neurology, University Medical Center Hamburg-Eppendorf, Germany ; Institute of Cognitive Neurology (INECO), Buenos Aires, Argentina ; Institute of Neuroscience, Favaloro University, Buenos Aires, Argentina.
authors.forename: Máximo
authors.initials: M
authors.lastname: Zimerman
authors.affiliation: Brain Imaging and NeuroStimulation (BINS) Laboratory, Department of Neurology, University Medical Center Hamburg-Eppendorf, Germany.
authors.forename: Maximilian J
authors.initials: MJ
authors.lastname: Wessel
authors.affiliation: Brain Imaging and NeuroStimulation (BINS) Laboratory, Department of Neurology, University Medical Center Hamburg-Eppendorf, Germany.
authors.forename: Jan E
authors.initials: JE
authors.lastname: Timmermann
authors.affiliation: Section for Neurofibromatosis, Department of Neurology, University Medical Center Hamburg-Eppendorf, Germany.
authors.forename: Sofia
authors.initials: S
authors.lastname: Granström
authors.affiliation: Brain Imaging and NeuroStimulation (BINS) Laboratory, Department of Neurology, University Medical Center Hamburg-Eppendorf, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Gerloff
authors.affiliation: Section for Neurofibromatosis, Department of Neurology, University Medical Center Hamburg-Eppendorf, Germany.
authors.forename: Victor F
authors.initials: VF
authors.lastname: Mautner
authors.affiliation: Brain Imaging and NeuroStimulation (BINS) Laboratory, Department of Neurology, University Medical Center Hamburg-Eppendorf, Germany ; Institute of Neuroscience, Favaloro University, Buenos Aires, Argentina.
authors.forename: Friedhelm C
authors.initials: FC
authors.lastname: Hummel
mesh_terms: D000328:Adult; D005260:Female; D006801:Humans; D007858:Learning; D017774:Long-Term Potentiation; D008297:Male; D008875:Middle Aged; D009044:Motor Cortex / Q000503:physiopathology*; D009433:Neural Inhibition; D009456:Neurofibromatosis 1 / Q000175:diagnosis / Q000378:metabolism / Q000503:physiopathology* / Q000523:psychology*; D011597:Psychomotor Performance; D050781:Transcranial Magnetic Stimulation; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D005680:gamma-Aminobutyric Acid
keywords: Motor Learning; NF1; SICI; TMS