Zimerman M., Wessel M., Timmermann J., Granström S., Gerloff C., Mautner VF., Hummel FC. Impairment of Procedural Learning and Motor Intracortical Inhibition in Neurofibromatosis Type 1 Patients. EBioMedicine. Sep 2015.

Impairment of Procedural Learning and Motor Intracortical Inhibition in Neurofibromatosis Type 1 Patients.

 

Autores Zimerman M., Wessel M., Timmermann J., Granström S., Gerloff C., Mautner VF., Hummel FC.
Año 2015
Journal EBioMedicine
Volumen 2015 Sep 1;2(10):1430-7
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.
FINDINGS:
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.
INTERPRETATIONS:
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.
Resumen Los trastornos en el aprendizaje son las complicaciones neurológicas mas frecuentes en pacientes con Neurofibromatosis tipo 1 (NF1).  En el presente estudio se cuantificó la modulación relacionada a la actividad GABAérgica de la corteza motora primaria (M1) durante un paradigma de aprendizaje extendido en NF1 sin déficits neuropsicológicos y normal funcionamiento en su actividades diaria profesional y privada. Se evidenció un deterioro en la adquisición de la habilidades motora mediada por una reducción selectiva en la adquisición temprana (online) y en la fase de consolidación (offline), con disminución en la modulación GABAergica. Estos resultados proporcionan los primeros indicios de que el aprendizaje procedural está deteriorado incluso en pacientes con NF1 clínicamente intactos y su relación con la disfunción cortical GABAérgica, con notables implicancias para futuras estrategias terapéuticas.