title: Different mechanisms contribute to motor cortex hyperexcitability in amyotrophic lateral sclerosis.
abstract: OBJECTIVE
  Different physiological approaches demonstrated motor system hyperexcitability in amyotrophic lateral sclerosis (ALS), probably reflecting excitotoxic mechanisms. Transcranial magnetic stimulation (TMS) showed that both increased excitability of corticomotoneurons and reduced intracortical inhibition (ICI) contribute to motor cortex hyperexcitability, but the importance of these factors in inducing this cortical dysfunction is unknown. The aim of the study was to establish how different mechanisms interact to promote motor system hyperexcitability in ALS in relation to clinical features.
  
  
  METHODS
  The resting motor threshold (RMT), the motor evoked potential (MEP) recruitment curve and the cortical silent period (CSP) to single-pulse TMS were evaluated in 35 patients with ALS. Early ICI and intracortical facilitation (ICF) and late ICI were evaluated by paired TMS.
  
  
  RESULTS
  The main abnormal TMS findings were: (a) a steeper MEP recruitment curve associated with a lowering of the RMT; (b) reduced or even absent early and late ICI; (c) reduced CSP lengthening with increasing TMS intensity. ICF was not affected. RMT increased and the MEP recruitment curve became less steep with longer disease duration, but they did not correlate with the motor deficit, the type of motoneuron affection and the decrease of ICI. Impairment of early and late ICI were significantly correlated to each other, to disease severity and to clinical evidence of upper motor neuron involvement.
  
  
  CONCLUSIONS
  Different and partially independent mechanisms contribute to motor cortex hyperexcitability in ALS. The increased gain in MEP recruitment with a lowering of the RMT appears to be a primary event reflecting an increase in the strength of corticospinal projections, probably related to changes in the ion-channel permeability of the neuronal membrane. On the other hand, inhibitory functions linked to multiple neurotransmitter systems decline with disease progression. Both depletion of specific subpopulations of intracortical GABAergic neurons and mechanisms involved in motor cortex reorganization following progressive neuronal loss have been considered to account for the impaired inhibition. The clarification of the importance of these factors in the pathogenesis of ALS may have diagnostic and therapeutic implications.
authors.affiliation: Department of Neurological Sciences and Vision, Section of Clinical Neurology, University of Verona, Ospedale Policlinico G.B. Rossi, piazzale Scuro, 37134 Verona, Italy. gi.zanette@libero.it
authors.forename: Giampietro
authors.initials: G
authors.lastname: Zanette
authors.forename: Stefano
authors.initials: S
authors.lastname: Tamburin
authors.forename: Paolo
authors.initials: P
authors.lastname: Manganotti
authors.forename: Nicola
authors.initials: N
authors.lastname: Refatti
authors.forename: Antonio
authors.initials: A
authors.lastname: Forgione
authors.forename: Nicola
authors.initials: N
authors.lastname: Rizzuto
mesh_terms: D000328:Adult; D000368:Aged; D000690:Amyotrophic Lateral Sclerosis / Q000503:physiopathology*; D018450:Disease Progression; D004576:Electromyography; D019054:Evoked Potentials, Motor / Q000502:physiology; D005260:Female; D006225:Hand / Q000294:innervation / Q000503:physiopathology; D006801:Humans; D008297:Male; D008875:Middle Aged; D009044:Motor Cortex / Q000503:physiopathology*; D009046:Motor Neurons / Q000502:physiology; D011597:Psychomotor Performance / Q000502:physiology; D011712:Pyramidal Tracts / Q000503:physiopathology; D011999:Recruitment, Neurophysiological / Q000502:physiology