Brain Advance Access published online on February 8, 2006
Brain, doi:10.1093/brain/awl024
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1 Department of Neurology, Graduate School of Medicine, Chiba University, Chiba, Japan
* To whom correspondence should be addressed. Fasciculations are a characteristic feature of amyotrophic lateral sclerosis (ALS), and can arise proximally or distally in the motor neuron, indicating a widespread disturbance in membrane excitability. Previous studies of axonal excitability properties (i.e. threshold electrotonus, strength-duration time constant) have suggested respectively that change in potassium or sodium channels may be involved. To reinvestigate these changes and explore their correlation with disease stage, multiple axonal excitability properties (threshold electrotonus, strength-duration time constant, recovery cycle and current-threshold relationship) were measured for the median nerve at the wrist in 58 ALS patients, and compared with 25 age-matched controls. In ALS, there were greater changes in depolarizing threshold electrotonus (i.e. less accommodation) (P < 0.001) and greater supernormality in the recovery cycles (P < 0.001). These abnormalities were more prominent in patients with moderately reduced CMAP (1-5 mV). Modelling the excitability changes in this group supported the hypothesis that axonal potassium conductances are reduced, resulting in increased supernormality despite membrane depolarization. The tendency for strength-duration time constant to be prolonged in ALS was only significant for patients with normal CMAP amplitude (>5 mV). Patients with severely reduced CMAP (<1 mV) alone showed reduced threshold changes to hyperpolarizing current. These results suggest a changing pattern of abnormal membrane properties with disease progression. First, persistent Na+ conductance increases, possibly associated with collateral sprouting, and then K+ conductances decline. Both changes cause axonal hyperexcitability, and may contribute to the generation of fasciculations. These serial changes in axonal properties could provide insights into the pathophysiology of ALS, and implications for future therapeutic options.
Received May 2, 2005
Revised November 16, 2005
Accepted November 17, 2005
Article
Altered axonal excitability properties in amyotrophic lateral sclerosis: impaired potassium channel function related to disease stage
Kazuaki Kanai 1 *,
Satoshi Kuwabara 1,
Sonoko Misawa 1,
Noriko Tamura 1,
Kazue Ogawara 1,
Miho Nakata 1,
Setsu Sawai 1,
Takamichi Hattori 1,
and
Hugh Bostock 2
2 Sobell Department of Neurophysiology, Institute of Neurology, London, UK
Kazuaki Kanai, E-mail: VZR03355{at}nifty.ne.jp
Abstract 
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  M. Moldovan, S. Alvarez, and C. Krarup Motor axon excitability during Wallerian degeneration Brain, February 1, 2009; 132(2): 511 - 523. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Burke, J. Howells, L. Trevillion, P. A. McNulty, S. K. Jankelowitz, and M. C. Kiernan Threshold behaviour of human axons explored using subthreshold perturbations to membrane potential J. Physiol., January 15, 2009; 587(2): 491 - 504. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Ng, J. Howells, J. D. Pollard, and D. Burke Up-regulation of slow K+ channels in peripheral motor axons: a transcriptional channelopathy in multiple sclerosis Brain, November 1, 2008; 131(11): 3062 - 3071. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Hegedus, C. T. Putman, N. Tyreman, and T. Gordon Preferential motor unit loss in the SOD1G93A transgenic mouse model of amyotrophic lateral sclerosis J. Physiol., July 15, 2008; 586(14): 3337 - 3351. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. U. Kleine, D. F. Stegeman, H. J. Schelhaas, and M. J. Zwarts Firing pattern of fasciculations in ALS: Evidence for axonal and neuronal origin Neurology, January 29, 2008; 70(5): 353 - 359. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Vucic and M. C. Kiernan Pathophysiologic insights into motor axonal function in Kennedy disease Neurology, November 6, 2007; 69(19): 1828 - 1835. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. K. Jankelowitz, J. Howells, and D. Burke Plasticity of inwardly rectifying conductances following a corticospinal lesion in human subjects J. Physiol., June 15, 2007; 581(3): 927 - 940. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Zona, M. Pieri, and I. Carunchio Voltage-Dependent Sodium Channels in Spinal Cord Motor Neurons Display Rapid Recovery From Fast Inactivation in a Mouse Model of Amyotrophic Lateral Sclerosis J Neurophysiol, December 1, 2006; 96(6): 3314 - 3322. [Abstract] [Full Text] [PDF]
|
|