Publications by authors named "Yoshiko Shibuta"

9 Publications

  • Page 1 of 1

Upregulation of axonal HCN current by methylglyoxal: Potential association with diabetic polyneuropathy.

Clin Neurophysiol 2015 Nov 14;126(11):2226-32. Epub 2015 Mar 14.

Department of Neurology, Tokushima University, Tokushima, Japan.

Objective: To describe functional changes of axonal ion channels by a metabolic derivative of glucose, methylglyoxal (MGO), and its potential contribution to diabetic neuropathy.

Methods: (1) In wild-type male mice, multiple excitability measurements of sensory nerves were performed at baseline and 1week after serial administration of MGO (50mg/kg). (2) Excitability testing in patients with diabetic neuropathy (N=17) and healthy controls (N=12) were also conducted, and data were interpreted using mathematical modeling.

Results: In the animal study, there was a decrease in threshold changes by long hyperpolarization and in superexcitability after administration of MGO. In the preliminary human study, the threshold changes by long hyperpolarizing current were decreased in patients with diabetes. Mathematical modeling showed increased hyperpolarization-activated cation current (Ih) in the MGO-treated mice and in patients with diabetes.

Conclusion: Ih was upregulated after MGO administration in normal mice.

Significance: MGO is associated with abnormal axonal excitability. Hyperexcitability in diabetic polyneuropathy may, at least in part, be caused by dysfunctional axonal hyperpolarization-activated cyclic nucleotide-gated (HCN) channels. A future study with a large sample size of the diabetic patients would clarify this hypothesis.
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http://dx.doi.org/10.1016/j.clinph.2015.02.058DOI Listing
November 2015

Abnormal gating of axonal slow potassium current in cramp-fasciculation syndrome.

Clin Neurophysiol 2015 Jun 28;126(6):1246-1254. Epub 2014 Sep 28.

Department of Neurology, Tokushima University, Tokushima, Japan.

Objective: Cramp-fasciculation syndrome (CFS) is a heterogeneous condition with multiple underlying causes. Although dysfunction of slow K(+) channels has been reported in patients with CFS, testing all potential candidates for this problem using conventional in vitro functional analysis would be prohibitively cost- and labor-intensive. However, relatively economical and non-invasive nerve-excitability testing can identify ion channel dysfunction in vivo when combined with numerical modeling.

Methods: Patients with CFS underwent nerve conduction study, needle electromyography, and nerve excitability testing. Mathematical modeling of axonal properties was applied to identify the pathophysiology.

Results: Four patients had distinct electrophysiological findings (i.e., fasciculation potentials, doublet/multiplet motor unit potentials, and sustained F responses); excitability testing showed the following abnormalities: reduction of accommodation during prolonged depolarization, lack of late sub excitability after a supramaximal stimulation, and reduction of the strength-duration time constant. Mathematical modeling showed a loss of voltage-dependence of a slow K(+) current. None of these patients had a mutation in the KCNQ2, 3, or 5 genes.

Conclusions: This study showed that patients with CFS might have abnormal kinetics in a slow K(+) current.

Significance: Nerve-excitability testing may aid the decision to start therapeutic intervention such as administration of slow K(+) channel openers.
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http://dx.doi.org/10.1016/j.clinph.2014.09.013DOI Listing
June 2015

Increased variability of axonal excitability in amyotrophic lateral sclerosis.

Clin Neurophysiol 2013 Oct 29;124(10):2046-53. Epub 2013 May 29.

Department of Neurology, Tokushima University, Tokushima, Japan.

Objective: Amyotrophic lateral sclerosis (ALS) is characterised by the increased excitability of motoneurons and heterogeneous loss of axons. The heterogeneous nature of the disease process among fibres may show variability of excitability in ALS.

Methods: Multiple nerve excitability tests were performed in 28 ALS patients and 23 control subjects, by tracking at the varying threshold levels (10%, 20%, 40% and 60% of maximum amplitudes).

Results: In normal controls, excitability measures at low target levels have the following characteristics compared to those at high target levels: longer strength-duration time constant, greater threshold reduction during depolarising currents and smaller threshold increase to hyperpolarising currents. ALS patients had less clear amplitude dependency of the parameters than the controls, indicating variability of axonal excitability. Three ALS patients demonstrated greater target-amplitude-dependent threshold changes in threshold electrotonus than controls, suggesting selective axonal hyperexcitability.

Conclusions: Some of the ALS patients had variable axonal excitability at different target amplitudes, suggesting preferential hyperexcitability in the axons with low target amplitude levels.

Significance: Variable membrane potentials of motor axons in ALS may be assessed by recording excitability testing at different target amplitude levels.
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http://dx.doi.org/10.1016/j.clinph.2013.02.117DOI Listing
October 2013

[Increased variability of membrane potentials in amyotrophic lateral sclerosis].

Rinsho Shinkeigaku 2011 Nov;51(11):1114-7

Department of Neurology, Tokushima University.

Amyotrophic lateral sclerosis (ALS) is characterized by increased excitability of motor neurons and early involvement of large motor fibers that have low electrical thresholds. Despite the advent of new techniques of threshold tracking, exploration of this abnormal excitability has not been straightforward, by tracking at the single target level as previous reported, because of the heterogeneous nature of the disease process among fibers that have variable thresholds. We have assessed different populations of motor axons by tracking at four different target response levels (10, 20, 40 and 60% of maximum compound muscle action potentials), and conducted multiple nerve excitability tests in 27 ALS patients and 23 control subjects. In normal controls, axons with low thresholds have the following characteristics compared to those with high thresholds: greater threshold reduction during depolarizing currents and smaller threshold increase to hyperpolarizing currents, reflecting the order of the fiber size. In contrast, ALS patients lacked these relationships, suggesting increased variability of axonal membrane potentials. Three ALS patients demonstrated changes in threshold electrotonus, consistent with overt membrane depolarization, as seen in ischemic nerves. The variability of motor nerve excitability accounts for fasciculations, confirms previously reported dysfunction of potassium channels, and suggests failure of Na(+)/K(+)pumps, possibly caused by mitochondrial dysfunctions at the early stage.
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http://dx.doi.org/10.5692/clinicalneurol.51.1114DOI Listing
November 2011

Can Awaji ALS criteria provide earlier diagnosis than the revised El Escorial criteria?

J Neurol Sci 2011 Mar 6;302(1-2):29-32. Epub 2011 Jan 6.

Department of Neurology, Tokushima University, Tokushima, Japan; Kansai Rehabilitation College, Hyogo, Japan.

Background: Recently, new electrophysiological ALS criteria incorporating fasciculation potentials (FPs) as evidence for lower motor neuron signs (Awaji Criteria (AC)) was proposed to provide earlier detection of early-stage ALS than revised El Escorial electrophysiological criteria (REEC). However, serial electrophysiological analysis is lacking to ascertain the original intention. The objective for this study was to elucidate whether electrophysiological criteria set for AC detects ALS earlier than REEC's counterpart in patients with ALS.

Methods: Of the 51 patients who were clinically suspected of ALS, 35 patients prospectively received serial electrophysiological studies every 3 months until (1) both electrophysiological AC and REEC criteria were met in more than two muscles representing both of the cervical and lumbosacral segments or (2) either clinically definite or clinically probable REEC criteria was met. The intervals were determined between the initial disease onset and when the respective electrophysiological criteria were met.

Results: Electrophysiological diagnostic criteria were met in 94.3% by AC and 40% by REEC at the initial visits. The intervals between the disease onset and the time of meeting the electrophysiological criteria were shorter in AC (mean: 9.0 months) than in REEC (mean: 15.2 months) (P<0.01). Eleven patients who met only AC electrophysiological criteria on the initial study subsequently met REEC electrophysiological criteria with the mean interval of 3.8 months. A higher percentage of bulbar-type ALS (83.3%) met AC than limb-onset ALS (43.4%) (P<0.05). FPs tended to be more frequently observed than fib/psw in the muscles outside the region of initial clinical onset.

Conclusion: Electrophysiological criteria of AC were met earlier than that of REEC in ALS patients, especially in patients with bulbar onset. Early recognition of ALS by AC may allow effective therapeutic intervention in the early disease stage.
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http://dx.doi.org/10.1016/j.jns.2010.12.007DOI Listing
March 2011

Peripheral nerve excitability measures at different target levels: the effects of aging and diabetic neuropathy.

J Clin Neurophysiol 2010 Oct;27(5):350-7

Department of Neurology, Tokushima University, Tokushima, Japan.

Threshold tracking testing has provided novel insights of peripheral nerve excitability in normal and pathologic conditions. However, little has been known on the nerve excitability properties of axons with different stimulation thresholds and the effects of aging and peripheral neuropathy to those. We performed multiple nerve excitability tests in normal controls divided into three age groups and in patients with diabetic neuropathy, which were recorded at three target levels (10%, 40%, and 60% of the maximum motor response amplitudes). In all the control groups, tracking at low target level shows smaller threshold change by hyperpolarizing stimuli and greater threshold change by depolarizing stimuli, suggestive of greater transient Na current. Normal elderly showed greater threshold change by hyperpolarizing pulse than younger subjects at high target level, likely reflecting decrease of axon diameters. Patients with diabetic neuropathy showed smaller threshold changes by both depolarizing and hyperpolarizing pulses ("fanning-in"), more noticeably at the lower target level, suggestive of the combined effects of membrane depolarization and greater decrease of axonal diameters in smaller fibers. Given the reported unpredictable electrical recruitment order in the diseased conditions and difference of nerve excitability measures in threshold electrotonus at different target levels, comparing threshold electrotonus values between normal and diseased axons may be problematic by comparing axons with different nerve excitability characteristics.
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http://dx.doi.org/10.1097/WNP.0b013e3181f387abDOI Listing
October 2010

Utility of recovery cycle with two conditioning pulses for detection of impaired axonal slow potassium current in ALS.

Clin Neurophysiol 2010 Dec 9;121(12):2117-20. Epub 2010 Jun 9.

Department of Neurology, Tokushima University, Tokushima, Japan.

Objective: Slow potassium current (I(Ks)) is important in controlling nerve excitability and its impairment is known in various neurological diseases, including amyotrophic lateral sclerosis (ALS). I(Ks) gives rise to the late subexcitability phase of the recovery cycle, which can be amplified by the use of multiple conditioning pulses. The clinical utility of this technique has not previously been explored.

Methods: Nerve excitability tests, including recovery cycles with single and double conditioning pulses 4ms apart (RC and RC2, respectively) were performed in patients with ALS and control subjects. Late subexcitability values obtained by RC and RC2 were compared in both groups.

Results: RC2 was well tolerated in all the subjects. The threshold changes in late subexcitability by RC2 were greater than those by RC in both groups (mean (%): RC, 16.0/13.3; RC2, 34.9/29.4 (Control/ALS)). The ALS group showed lower threshold changes than controls by both methods. Statistical analysis between the ALS and control groups provided smaller P value by RC2 (P=0.018) than by RC (P=0.046). Also, RC2 provided non-significant, but slightly more distinguishing non-parametric rank analysis and greater Area Under the Curve (AUC) by Receiver Operating Characteristic (ROC). RC2 produced more identifiable single peak for late subexcitability than RC in an ALS patient whose late subexcitability was decreased.

Conclusions: Two conditioning stimuli provide greater threshold change for late subexcitability and possibly clearer identification of a peak threshold change than conventional recovery cycle. The findings obtained by this new protocol reinforce the previously reported impairment of I(Ks) in ALS.

Significance: Amplification of I(Ks) by double conditioning pulses is applicable in humans and may help elucidating its clinical significance in pathophysiology in neurological diseases.
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http://dx.doi.org/10.1016/j.clinph.2010.05.015DOI Listing
December 2010

Threshold-dependent effects on peripheral nerve in vivo excitability properties in the rat.

Neurosci Lett 2010 Jan 10;468(3):248-53. Epub 2009 Nov 10.

Department of Neurology, Tokushima University, Tokushima, Japan.

Various factors, including maturity, have been shown to influence peripheral nerve excitability measures, but little is known about differences in these properties between axons with different stimulation thresholds. Multiple nerve excitability tests were performed on the caudal motor axons of immature and mature female rats, recording from tail muscles at three target compound muscle action potential (CMAP) levels: 10%, 40% ("standard" level), and 60% of the maximum CMAP amplitude. Compared to lower target levels, axons at high target levels have the following characteristics: lower strength-duration time constant, less threshold reduction during depolarizing currents and greater threshold increase to hyperpolarizing currents, most notably to long hyperpolarizing currents in mature rats. Threshold-dependent effects on peripheral nerve excitability properties depend on the maturation stage, especially inward rectification (Ih), which becomes inversely related to threshold level. Performing nerve excitability tests at different target levels is useful in understanding the variation in membrane properties between different axons within a nerve. Because of the threshold effects on nerve excitability and the possibility of increased variability between axons and altered electric recruitment order in disease conditions, excitability parameters measured only at the "standard" target level should be interpreted with caution, especially the responses to hyperpolarizing currents.
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http://dx.doi.org/10.1016/j.neulet.2009.11.006DOI Listing
January 2010
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