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Biomedical subjects

Kazue Ogawara

Publications and source records attributed to Kazue Ogawara.

At least 19 recordsLinked to original sources
PubMed2006

Latent addition in human motor and sensory axons: different site-dependent changes across the carpal tunnel related to persistent Na+ currents.

OBJECTIVE: To compare site-dependent changes across the carpal tunnel in axonal persistent Na+ conductances in motor and sensory axons. Positive sensory symptoms are prominent features in carpal tunnel syndrome, and a persistent Na+ current is a major determinant of axonal excitability. METHODS: The technique of latent addition was used to estimate persistent Na+ currents in median motor and sensory axons at the wrist and palm of 10 normal subjects. Brief hyperpolarizing conditioning current pulses were delivered, and threshold change at the conditioning-test interval of 0.2 ms was measured as an indicator of persistent Na+ currents. RESULTS: Threshold changes at 0.2 ms were greater in sensory than in motor axons at both the wrist and palm. In motor axons, the threshold changes were significantly smaller at the palm (mean, 4.9%) than at the wrist (10.0%). By contrast, the threshold changes were similar at the two sites of sensory axons (12.6 and 13.1%). The passive membrane time constant was similar for motor and sensory axons at the palm and wrist. CONCLUSIONS: Nodal persistent Na+ conductances have substantial site-dependent changes decreasing distally across the carpal tunnel in median motor axons, but not in sensory axons. SIGNIFICANCE: Whereas sensory axons generally have higher excitability than motor axons, the sensory-motor differences become more prominent across, and possibly at the carpal tunnel than the nerve trunk, and it is suggested that this contributes to the predominance of positive sensory symptoms in carpal tunnel syndrome.

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PubMed2006

Nodal persistent Na+ currents in human diabetic nerves estimated by the technique of latent addition.

OBJECTIVE: To investigate the effects of hyperglycemia on persistent Na+ currents in human diabetic nerves, eliminating the factors of passive membrane properties as a factor. Previous studies show that strength-duration time constant of a nerve is shortened under hyperglycemia, suggesting reduced axonal persistent Na+ currents. However, the time constant is also affected by changes in passive membrane properties. Latent addition using computerized threshold tracking is a new method that can separately evaluate Na+ currents and passive membrane properties. METHODS: Latent addition was used to estimate nodal Na+ currents in median motor axons of 83 diabetic patients. Brief hyperpolarizing conditioning current pulses were delivered, and threshold changes at the conditioning-test interval of 0.2 ms were measured as an indicator of nodal persistent Na+ currents. Seventeen patients were examined before and after insulin treatment. RESULTS: There was an inverse linear relationship between hemoglobin A1c levels and threshold changes at 0.2 ms (P=0.02); the higher hemoglobin A1c levels were associated with smaller threshold changes. After insulin treatment, there was a significant improvement in nerve conduction velocities associated with greater threshold changes at 0.2 ms (P=0.03), suggesting an increase in persistent Na+ currents. The fast component of latent addition, an indicator of passive membrane properties, was not affected by the state of glycemic control. CONCLUSIONS: Hyperglycemia could suppress nodal persistent Na+ currents, presumably because of reduced trans-axonal Na+ gradient or impaired Na+ channels, and this can be rapidly restored by glycemic control. SIGNIFICANCE: Reduced nodal Na+ currents may partly contribute to the pathophysiology of human diabetic neuropathy.

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PubMed2006

Altered axonal excitability properties in amyotrophic lateral sclerosis: impaired potassium channel function related to disease stage.

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.

Adult↗
PubMed2005

Strength-duration properties and glycemic control in human diabetic motor nerves.

OBJECTIVE: To investigate the influences of hyperglycemia on axonal excitability in human diabetic nerves. Hyperglycemia results in decreased Na+-K+ pump function, presumably leading to intra-axonal Na+ accumulation and thereby, reduced Na+ currents. METHODS: The strength-duration time constant (tau(SD)), which partly depends on persistent Na+ conductance active at the resting membrane potential, was measured in median motor axons of 79 diabetic patients. The relationship of tau(SD) with the state of glycemic control (hemoglobin A1c [HbA1c] levels) was analyzed. RESULTS: The mean tau(SD) was longer for diabetic patients than for normal controls, but the difference was not significant. Among diabetic patients, the subgroup of patients with good glycemic control (HbA1c<7%) had significantly longer tau(SD) than the patient group with poor control (HbA1c>9%; P=0.04). The mean tau(SD) was longest at the HbA1c level of 5-6%, gradually decreasing and reaching a plateau around the HbA1c level of 9%. There was an inverse relationship between HbA1c levels and tau(SD), when the HbA1c levels ranged from 5 to 9% (P=0.04). CONCLUSIONS: In diabetic nerves, tau(SD) is generally longer than normal, but hyperglycemia is associated with paradoxically shortened tau(SD), because of a decrease in axonal persistent Na+ conductance, possibly related to reduced membranous Na+ gradient, tissue acidosis, or other metabolic factors. SIGNIFICANCE: Measurements of tau(SD) could provide a new insight into changes in ionic conductance in human diabetic nerves.

Adult↗
PubMed2005

The acute effects of glycemic control on nerve conduction in human diabetics.

OBJECTIVE: To investigate acute changes in nerve conduction associated with glycemic control. In diabetes, nerve dysfunction can result from reversible metabolic factors associated with hyperglycemia, as well as structural changes. METHODS: Multiple nerve conduction parameters including F-wave latencies were measured in 47 diabetic patients with prominent hyperglycemia before and after intensive insulin treatment. RESULTS: Four weeks after the start of treatment, there was a significant improvement in minimal F-wave latencies of the median (P<0.001) and tibial (P<0.001) nerves, and in distal latencies (P=0.01) and sensory nerve conduction velocities (P<0.001) of the median nerves. Amplitudes of motor and sensory responses did not change significantly. These findings were similar for patients with type 1 (n=8) and those with type 2 (n=39) diabetes. Patients with poorer glycemic control or milder neuropathy tended to show greater changes after treatment. CONCLUSIONS: Glycemic control quickly alters the speed of nerve conduction. F-wave latencies and conduction times across the carpal tunnel are very sensitive parameters. SIGNIFICANCE: Serial nerve conduction studies can detect reversible slowing of nerve conduction presumably caused by metabolic factors, such as decreased Na+/K+-ATPase activity, the altered polyol pathway, and tissue acidosis.

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PubMed2005

The effects of mexiletine on excitability properties of human median motor axons.

OBJECTIVE: To investigate the effects of mexiletine, an analog of lidocaine, on excitability of human axons in vivo. METHODS: Threshold tracking was used to measure multiple excitability indices (strength-duration time constant, rheobase, refractoriness, supernormality, and threshold electrotonus) in median motor axons of 20 patients with neuropathic pain or muscle cramping, before and 3 months after treatment with oral 300 mg mexiletine per day. RESULTS: After treatment, there was a reduction in pain/muscle cramps, associated with decreased strength-duration time constants (P=0.01), increased rheobasic currents (P=0.06), and lower refractoriness (P=0.02), all of which were consistent with reduced nodal Na+ currents. Supernormality and threshold electrotonus did not change significantly. The changes in strength-duration properties suggest a decrease in persistent Na+ conductance. The lowered refractoriness after treatment might result from reduced transient Na+ currents, but the lack of change in supernormality and threshold electrotonus was not consistent with this hypothesis. CONCLUSIONS: Oral mexiletine in a dosage of 300 mg daily suppresses persistent Na+ currents in human motor axons. SIGNIFICANCE: Measurements of the excitability indices can be used for non-invasive assessment and monitoring of the effects of mexiletine in patients with neuropathic pain or muscle cramps.

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PubMed2005

Axonal potassium conductance and glycemic control in human diabetic nerves.

OBJECTIVE: To investigate the effects of hyperglycemia on axonal excitability and potassium conductance in human diabetic nerves. METHODS: Threshold tracking was used to measure excitability indices, which depend on potassium channels (supernormality, late subnormality, threshold electrotonus, and a current/threshold relationship) in median motor axons of 96 diabetic patients. The effects of hyperglycemia on these indices were analyzed. RESULTS: Among diabetic patients, higher serum hemoglobin A1c (HbA1c) levels were significantly associated with greater supernormality (P = 0.04) and smaller late subnormality (P = 0.02), suggestive of reduced nodal/paranodal potassium currents under hyperglycemia. Threshold electrotonus and current/threshold relationships did not correlate with HbA1c levels, but partly related with nerve conduction slowing. CONCLUSIONS: Hyperglycemia could reduce nodal potassium conductances, possibly due to reduced membranous potassium gradient or suppression of potassium channels. In contrast, internodal potassium conductances may be determined by both metabolic factors and structural changes such as exposure of internodal channels by demyelination. SIGNIFICANCE: Measurements of the excitability indices could provide new insights into nodal and internodal axonal membrane properties in human diabetic neuropathy, whereas multiple factors can affect especially internodal properties.

Adult↗
PubMed2004

Sensory nerve conduction in demyelinating and axonal Guillain-Barré syndromes.

Guillain-Barré syndrome is divided into acute inflammatory demyelinating polyneuropathy (AIDP) and acute motor axonal neuropathy (AMAN) based on motor nerve conduction studies. We investigated whether sensory nerve conduction studies contribute to the electrodiagnosis of AIDP and AMAN. In consecutive 59 patients with AIDP (n = 26) or AMAN (n = 33), results of sensory nerve conduction studies in the median, ulnar and sural nerves were reviewed. Sensory nerve conduction abnormalities were found for 85% of AIDP patients and for only 6% of AMAN patients. In AIDP patients, the abnormalities were present in 85% of patients in the median nerves, 85% in the ulnar nerves and 38% in the sural nerves. AMAN is very rarely associated with sensory nerve involvement. Abnormal sensory nerve conduction is supportive of AIDP and is more frequently found for the median and ulnar nerves than sural nerves.

Adolescent↗
PubMed2004

The acute effects of glycemic control on axonal excitability in human diabetics.

In diabetic nerves, the activation of the polyol pathway and a resulting decrease in Na(+)-K(+) ATPase activity lead to intra-axonal Na(+) accumulation and a smaller Na(+) gradient across the axolemma than normal. To investigate whether glycemic control is associated with acutely reversible changes in axonal excitability and Na(+) conductance, we measured the multiple excitability indices (strength-duration time constant, rheobase, refractoriness, and refractory period) of the median motor axons of 21 diabetic patients before and after intensive insulin treatment. Within 4 weeks after treatment was begun, there was a significant improvement in nerve conduction velocities, associated with increased strength-duration time constant, decreased rheobase, increased refractoriness, and prolonged refractory periods. Assuming that the strength-duration time constant partly reflects persistent Na(+) conductance, and that refractoriness/refractory periods depend on inactivation of transient Na(+) channels caused by prior depolarization (the influx of Na(+)), the patterns of changes in these indices may reflect a reduced trans-axonal Na(+) gradient during hyperglycemia and its restoration by glycemic control in diabetic patients. Measurement of the excitability indices could provide new insights into the pathophysiology of human diabetic neuropathy.

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PubMed2004

Threshold electrotonus in chronic inflammatory demyelinating polyneuropathy: correlation with clinical profiles.

Chronic inflammatory demyelinating polyneuropathy (CIDP) is characterized by multifocal demyelination along the course of the nerves, and involvement of the intermediate segments may correlate with more severe demyelination associated with breakdown of the blood-nerve barrier. Threshold electrotonus was used to study whether altered membrane properties of the median nerve at the wrist (intermediate segment) are associated with clinical profiles in 21 CIDP patients. In response to hyperpolarizing conditioning stimuli, the threshold changes were significantly greater for CIDP patients than for normal controls (n = 49). The pattern was similar to that of 11 patients with Charcot-Marie-Tooth disease type 1a, who exhibited abnormally high thresholds to hyperpolarizing currents. The abnormal threshold electrotonus was present in 48% of the CIDP patients and was associated with longer disease duration, more severe disability, poorer response to immune treatments, and slower nerve conduction velocities. Threshold electrotonus can be used to detect demyelination at the tested sites and may provide new information about pathophysiology and distribution patterns of demyelination in CIDP.

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PubMed2004

Excitability properties of human median axons measured at the motor point.

Threshold tracking was used to measure excitability indices (strength-duration properties, threshold electrotonus, and the current-threshold relationship) at the motor point of the abductor pollicis brevis, and the results were compared with those of the median nerve at the wrist. Using an accelerometer placed at the thumb tip, movement-related potentials were recorded as target responses. When stimulating at the same site, excitability measurements were no different, and their variability no greater, when the target responses were movements rather than muscle action potentials. Motor point stimulation resulted in significantly shorter strength-duration time-constant and higher rheobase than wrist stimulation. In addition, the technique of latent addition showed that a slow component was much smaller at the motor point than at the wrist. In threshold electrotonus, threshold changes in response to depolarizing and hyperpolarizing conditioning currents were significantly smaller at the motor point than at the wrist. The differences in strength-duration time-constant and latent addition suggest that persistent Na(+) current at the resting potential is smaller at the motor point. The differences in threshold electrotonus may depend in part on altered fiber geometry but suggest that inward and possibly outward rectification are increased distally. Motor point excitability testing may provide new insights into the pathophysiology of the nerve terminals in a variety of peripheral neuropathies and motor neuron disorders.

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PubMed2004

Hyperglycemia alters refractory periods in human diabetic neuropathy.

OBJECTIVE: To investigate the effects of hyperglycemia on axonal excitability in human diabetics. Diabetic nerve dysfunction is partly associated with the altered polyol pathway and Na+-K+ ATPase activity, probably resulting in a decrease in the trans-axonal Na+ gradient and reduced nodal Na+ currents. METHODS: Threshold tracking was used to measure the relative refractory periods (RPs) of median motor axons in 58 diabetic patients, 45 normal subjects, and 12 patients with non-diabetic axonal neuropathy. In diabetic patients, the relationship of RPs with hemoglobin A1c (HbA1c) levels was analyzed. RESULTS: The mean RP was similar for diabetics and normal controls as a group, but was longer in patients with non-diabetic neuropathy than in normal controls (P=0.02). Diabetic patients with good glycemic control (HbA1c levels <7%) had longer RPs than patients with poorer glycemic control and normal controls (P=0.01). RP was longest at the HbA1c level of 6%, gradually decreasing and reaching a plateau at the HbA1c level of 8-9%. CONCLUSIONS: Hyperglycemia shortens RPs, possibly because metabolic abnormalities lead to reduced nodal Na+ currents, and thereby to a lower inactivation of Na+ channels when generating an action potential. SIGNIFICANCE: RP measurements could provide new insights into the ionic pathophysiology of human diabetic neuropathy.

Adult↗
PubMed2003

Nerve excitability properties in Charcot-Marie-Tooth disease type 1A.

Charcot-Marie-Tooth disease type 1A (CMT1A) is commonly considered a prototype of a hereditary demyelinating polyneuropathy. Apart from the myelin involvement, there has been little information on axonal membrane properties in this condition. Taking advantage of the uniform nature of the disease process, we undertook the in vivo assessment of multiple axonal excitability properties at the median nerve in nine CMT1A patients with PMP22 (peripheral myelin protein 22) gene duplication and 53 controls. The thresholds of CMT1A patients were much higher than normal, and threshold electrotonus (TE) exhibited a consistent pattern of abnormalities: early steep changes (fanning out) of both hyperpolarizing and depolarizing responses were followed by increased inward rectification to hyperpolarizing currents and unusually fast accommodation to depolarizing currents. Strength-duration time constants and the shapes of recovery cycles were normal, although refractoriness and superexcitability were reduced relative to controls. The high thresholds and early fanning out of electrotonus indicated altered cable properties, such that a greater proportion than normal of applied currents reached internodal rather than nodal axolemma. The rapid accommodation to depolarizing currents suggested activation of fast K+ channels, which are normally sequestered from the nodal membrane. The excitability abnormalities are therefore consistent with a demyelinating pathology and exposure or spread of K+ channels from under the myelin. It remains to be seen whether the TE abnormalities in CMT1A, which resemble previous recordings from normal immature rats, can be distinguished from those in acquired demyelinating neuropathies.

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PubMed2003

Anti-GM1b IgG antibody is associated with acute motor axonal neuropathy and Campylobacter jejuni infection.

Anti-GM1 and anti-GM1b antibodies are frequently present in patients with Guillain-Barré syndrome (GBS) and accordingly, the two antibodies often coexist in the same patient. In order to study clinical and laboratory features of anti-GM1b-positive GBS, we analyzed the data of patients with anti-GM1b IgG antibody but no anti-GM1 IgG antibody. Of 86 consecutive patients, 10 had anti-GM1b antibody alone and frequently had acute motor axonal neuropathy (AMAN, 80%) and Campylobacter jejuni infection (60%). Of 10 patients with anti-GM1 antibody alone, four had AMAN, and two had C. jejuni infection. These results showed that GM1b could be a target molecule of autoantibody in the AMAN form of GBS subsequent to C. jejuni infection.

Adolescent↗
PubMed2003

The refractory period of transmission is impaired in axonal Guillain-Barré syndrome.

Guillain-Barré syndrome (GBS) is classified as acute motor axonal neuropathy (AMAN) or acute inflammatory demyelinating polyneuropathy (AIDP). Motor nerve conduction block is frequently found in both subtypes of GBS. To compare patterns of conduction block and the safety factor for impulse transmission in AMAN and AIDP, pairs of supramaximal stimuli at intervals of 1-5 ms were delivered to stimulate the median nerve at the wrist. At the 2- and 3-ms intervals, compound muscle action potentials (CMAPs) to the second stimulus were significantly smaller in AMAN patients (n = 7) than in normal subjects (n = 10) and AIDP patients (n = 6). Over 4 weeks from onset, the amplitude of both conditioned and unconditioned CMAPs returned toward normal, consistent with improvement in the safety factor for impulse transmission. The refractory period of transmission is impaired in AMAN, and the site of transmission failure is likely to be the motor nerve terminals. In addition to axonal degeneration, the critically but reversibly reduced safety factor is important in the pathophysiology of AMAN, and consistent with the rapid resolution of distal conduction block often seen in AMAN patients.

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PubMed2003

Muscle cramp in Machado-Joseph disease: altered motor axonal excitability properties and mexiletine treatment.

Machado-Joseph disease is one of the most common hereditary spinocerebellar degenerative disorders with a wide range of clinical manifestations. Pathology studies have shown mild to moderate loss of anterior horn cells and, in terms of spinal pathology, Machado-Joseph disease is regarded as a type of lower motoneuron disease. Muscle cramps are often associated with lower motoneuron disorders, but features of cramps in Machado-Joseph disease patients have never been studied. We investigated the incidence and nature of muscle cramps in Machado-Joseph disease patients, the excitability properties of motor axons [strength-duration time constant (tau(SD)), threshold electrotonus, refractoriness and supernormality] using threshold tracking and the effects of mexiletine hydrochloride on those cramps. Of 20 consecutive patients, 16 (80%) had frequent, severe muscle cramps in the legs, trunk or arms that disturbed their daily activities. The frequency of pathological muscle cramps was similar to that for patients with amyotrophic lateral sclerosis (68%) and higher than those for patients with spinal muscular atrophy (33%) or peripheral axonal neuropathy (24%). Threshold-tracking studies showed that tau(SD), which in part reflects Na(+) conductance at the resting membrane potential, was significantly greater in the Machado-Joseph disease patients than in normal subjects; severe muscle cramps were associated with a longer tau(SD). Threshold electrotonus, refractoriness and supernormality were not significantly different between Machado-Joseph disease patients and normal subjects. Eight Machado-Joseph disease patients with severe cramps, who received mexiletine treatment, experienced nearly complete relief with a partial normalization of tau(SD) (P = 0.08). Muscle cramps are a very frequent and disabling factor in Machado-Joseph disease. Pathological muscle cramps responded well to mexiletine treatment, and this is consistent with the hypothesis that they are caused by an increase in persistent Na(+) conductance, possibly associated with axonal regeneration or collateral sprouting.

Adolescent↗