Excitability of sensory axons in amyotrophic lateral sclerosis

Objective

To evaluate the excitability of sensory axons in patients with amyotrophic lateral sclerosis (ALS).

Progressive axonal dysfunction and clinical impairment in amyotrophic lateral sclerosis

Objective

To elucidate longitudinal changes in axonal function in amyotrophic lateral sclerosis (ALS) patients, and to relate such changes with motor unit loss and functional impairment.

Methods

37 ALS patients (age, 53.7 ± 1.7 years; 22 males) were studied using axonal excitability techniques at baseline and 12 weeks follow-up.

Results

Longitudinal measurements across excitability parameters suggested increasing K⁺ channel dysfunction, with further increases in depolarising threshold electrotonus (90–100 ms, baseline, 46.8 ± 1.0%; follow-up, 48.7 ± 0.8%; P = 0.02) and superexcitability (baseline, −24.0 ± 1.2%; 12 weeks, −26.0 ± 1.2%; P = 0.04). Patients with preserved compound muscle action potential (CMAP) amplitude at follow-up developed more severe changes in axonal excitability than those in whom CMAP decreased from baseline, suggesting that the most pronounced disease effects were on motor axons immediately prior to axonal loss in ALS patients. Fine motor decline was associated with more severe changes in axonal excitability, suggesting that functional impairment was related to axonal dysfunction.

Conclusions

Longitudinal changes in axonal excitability in ALS patients suggest increasing K⁺ channel dysfunction in motor axons.

Significance

Axonal excitability studies enable investigation of longitudinal changes in axonal ion channel dysfunction, and thereby the processes that potentially contribute to axonal degeneration in ALS.     

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

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 4 ms 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.     

Ectopic impulse generation in peripheral nerve hyperexcitability syndromes and amyotrophic lateral sclerosis

Objective

To elucidate differences in the distribution and firing frequency of fasciculations between peripheral nerve hyperexcitability syndromes and amyotrophic lateral sclerosis (ALS) and to explore the generator site of fasciculations.

Correlation between compound muscle action potential amplitude and duration in axonal and demyelinating polyneuropathy

Objective

To get a better understanding of pathophysiology in polyneuropathies (PNPs) by correlating compound muscle action potential (CMAP) amplitude with duration.

Methods

A total of 145 motor nerve conduction studies (MNCS) in 53 axonal and 132 MNCS in 45 demyelinating PNPs were analyzed. Peroneal and tibial MNCS were done by surface stimulation while for median and ulnar nerves near nerve or surface stimulations were used. CMAP amplitude and duration were compared in axonal and demyelination PNPs. Relationships between amplitude and duration of distally and proximally evoked CMAP were examined using regression analysis.

Results

CMAP amplitude was lower and duration was increased in all examined nerves in demyelinating PNPs than in axonal PNPs. In demyelinating PNPs, an inverse linear correlation between amplitude and duration was seen in distally and proximally evoked CMAP in all examined nerves. In axonal PNPs, there was no correlation in any of the nerves neither in distally nor in proximally evoked CMAP.

Conclusions

Distal CMAP duration and the relationship between CMAP amplitude and duration show supplementary electrodiagnostic potential in demyelinating PNPs.

Significance

More knowledge about the relation between amplitude and duration in axonal lesions and demyelination may help to reveal the pathophysiology in PNPs. Significant correlation between amplitude and duration in demyelination may suggest that the severe decrease in amplitude in demyelinating PNPs is probably due to the increase in duration secondary to temporal dispersion.     

Corticomotor excitability of arm muscles modulates according to static position and orientation of the upper limb

Objective

We investigated how multi-joint changes in static upper limb posture impact the corticomotor excitability of the posterior deltoid (PD) and biceps brachii (BIC), and evaluated whether postural variations in excitability related directly to changes in target muscle length.

Methods

The amplitude of individual motor evoked potentials (MEPs) was evaluated in each of thirteen different static postures. Four functional postures were investigated that varied in shoulder and elbow angle, while the forearm was positioned in each of three orientations. Posture-related changes in muscle lengths were assessed using a biomechanical arm model. Additionally, M-waves were evoked in the BIC in each of three forearm orientations to assess the impact of posture on recorded signal characteristics.

Results

BIC-MEP amplitudes were altered by shoulder and elbow posture, and demonstrated robust changes according to forearm orientation. Observed changes in BIC-MEP amplitudes exceeded those of the M-waves. PD-MEP amplitudes changed predominantly with shoulder posture, but were not completely independent of influence from forearm orientation.

Conclusions

Results provide evidence that overall corticomotor excitability can be modulated according to multi-joint upper limb posture.

Significance

The ability to alter motor pathway excitability using static limb posture suggests the importance of posture selection during rehabilitation aimed at retraining individual muscle recruitment and/or overall coordination patterns.     

Impact of pulse duration in single pulse TMS

Objective

The intensity of transcranial magnetic stimulation (TMS) is typically adjusted by changing the amplitude of the induced electrical field, while its duration is fixed. Here we examined the influence of two different pulse durations on several physiological parameters of primary motor cortex excitability obtained using single pulse TMS.

Methods

A Magstim Bistim² stimulator was used to produce TMS pulses of two distinct durations. For either pulse duration we measured, in healthy volunteers, resting and active motor thresholds, recruitment curves of motor evoked potentials in relaxed and contracting hand muscles as well as contralateral (cSP) and ipsilateral (iSP) cortical silent periods.

Results

Motor thresholds decreased by 20% using a 1.4 times longer TMS pulse compared to the standard pulse, while there was no significant effect on threshold adjusted measurements of cortical excitability. The longer pulse duration reduced pulse-to-pulse variability in cSP.

Conclusions

The strength of a TMS pulse can be adjusted both by amplitude or pulse duration. TMS pulse duration does not affect threshold-adjusted single pulse measures of motor cortex excitability.

Significance

Using longer TMS pulses might be an alternative in subjects with very high motor threshold. Pulse duration might not be relevant as long as TMS intensity is threshold-adapted. This is important when comparing studies performed with different stimulator types.     

Quantitative studies of lower motor neuron degeneration in amyotrophic lateral sclerosis: Evidence for exponential decay of motor unit numbers and greatest rate of loss at the site of onset

Objective

To use our Bayesian method of motor unit number estimation (MUNE) to evaluate lower motor neuron degeneration in ALS.

Methods

In subjects with ALS we performed serial MUNE studies. We examined the repeatability of the test and then determined whether the loss of MUs was fitted by an exponential or Weibull distribution.

Results

The decline in motor unit (MU) numbers was well-fitted by an exponential decay curve. We calculated the half life of MUs in the abductor digiti minimi (ADM), abductor pollicis brevis (APB) and/or extensor digitorum brevis (EDB) muscles. The mean half life of the MUs of ADM muscle was greater than those of the APB or EDB muscles. The half-life of MUs was less in the ADM muscle of subjects with upper limb than in those with lower limb onset.

Conclusions

The rate of loss of lower motor neurons in ALS is exponential, the motor units of the APB decay more quickly than those of the ADM muscle and the rate of loss of motor units is greater at the site of onset of disease.

Significance

This shows that the Bayesian MUNE method is useful in following the course and exploring the clinical features of ALS.     

Abnormal cortical brain integration of somatosensory afferents in ALS

Objectives

Infraclinical sensory alterations have been reported at early stages of amyotrophic lateral sclerosis (ALS). While previous studies mainly focused on early somatosensory evoked potentials (SEPs), late SEPs, which reflect on cortical pathways involved in cognitive-motor functions, are relatively underinvestigated. Early and late SEPs were compared to assess their alterations in ALS.

Phrenic nerve studies predict survival in amyotrophic lateral sclerosis

Objective

Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disease associated with short survival due to respiratory failure. We aimed to test the predictive value of the phrenic nerve motor response for survival, in a large population of ALS patients.

Methods

We included 254 ALS patients followed in our tertiary centre from 1997 to 2006, in whom phrenic nerve stimulation was performed according to the study inclusion and exclusion criteria. ALS was spinal onset in 175 and bulbar onset in 79 patients. The following features were recorded at entry: gender, age at presentation, onset region, diagnostic delay, forced vital capacity (FVC), ALS functional rating scale (ALS-FRS) including the respiratory subscore of the reviewed ALS-FRS and mean amplitude of motor responses by phrenic nerve stimulation (PhrenAmpl).

Results

Survival analysis was evaluated by Kaplan–Meier log-rank test and multivariate Cox proportional hazards. Independent factors negatively affecting survival were bulbar onset, short diagnostic delay, FVC and small PhrenAmpl for the total population. Small PhrenAmpl and short diagnostic delay were also independent factors for both spinal and bulbar-onset patients; age at onset and FVC were also independent predictors in bulbar-onset patients.

Conclusion

Phrenic nerve stimulation is a non-volitional test that can be performed quickly in most patients; it is a powerful predictor of survival in ALS.

Significance

Phrenic nerve stimulation should be considered as an additional test for respiratory assessment in ALS.     

Altered motor axonal excitability in patients with cervical spondylotic amyotrophy

Objective

To investigate the changes in motor axonal excitability properties in cervical spondylotic amyotrophy (CSA).

An exploratory model for G × E interaction on hippocampal volume in schizophrenia; obstetric complications and hypoxia-related genes

Background

Smaller hippocampal volume has repeatedly been reported in schizophrenia patients. Obstetric complications (OCs) and single nucleotide polymorphism (SNP) variation in schizophrenia susceptibility genes have independently been related to hippocampal volume. We investigated putative independent and interaction effects of severe hypoxia-related OCs and variation in four hypoxia-regulated schizophrenia susceptibility genes (BDNF, DTNBP1, GRM3 and NRG1) on hippocampal volume in schizophrenia patients and healthy controls.

Methods

Clinical assessment, structural MRI scans, and blood samples for genotyping of 32 SNPs were obtained from 54 schizophrenia patients and 53 control subjects. Information on obstetric complications was collected from original birth records.

Results

Severe OCs were related to hippocampal volume in both patients with schizophrenia and healthy control subjects. Of the 32 SNPs studied, effects of severe OCs on hippocampal volume were associated with allele variation in GRM3 rs13242038, but the interaction effect was not specific for schizophrenia. SNP variation in any of the four investigated genes alone did not significantly affect hippocampal volume.

Conclusions

The findings suggest a gene–environment (G × E) interaction between GRM3 gene variants and severe obstetric complications on hippocampus volume, independent of a diagnosis of schizophrenia. Due to the modest sample size, the results must be considered preliminary and require replication in independent samples.     

Outcome of Chlamydia pneumoniae associated acute ischemic stroke in elderly patients: a case-control study

Background

Limited data exists about the role of Chlamydia pneumoniae elderly patients with acute ischemic stroke.

Objective

To study the role of C. pneumoniae in elderly patients (age more than 65 years) with acute ischemic stroke and its impact on stroke out come.

Methods

We recruited 100 elderly patients with acute ischemic stroke and 100 age and sex matched controls over a period of 2 years. IgG and IgA anti C. pneumoniae antibodies were measured by microimmunofluorescence technique in patients and controls. Good outcome was defined as a Modified Rankin score (mRS) of ≤2.

Results

We found C. pneumoniae antibodies in 35% stroke patients and in 18% control subjects (p = 0.01). Good out come at 90 days follow up was found in 20/35(57.1%) seropositive stroke patients compared to 37/65(56.9%) seronegative stroke patients (p = 0.9).

Conclusions

C. pneumoniae antibody positivity was independently associated with ischemic stroke in elderly patients and its presence does not alter the stroke outcome.     

A functional polymorphism in estrogen receptor alpha gene is associated with Japanese methamphetamine induced psychosis

Background

A recent study reported an association between rs2234693, which influences enhancer activity levels in estrogen receptor alpha gene (ESR1), and schizophrenia. This study reported that schizophrenic patients with the CC genotype have significantly lower ESR1 mRNA levels in the prefrontal cortex than patients with other genotypes. The symptoms of methamphetamine induced psychosis are similar to those of paranoid type schizophrenia. Therefore, we conducted an association analysis of rs2234693 with Japanese methamphetamine induced psychosis patients.

Method

Using rs2234693, we conducted a genetic association analysis of case-control samples (197 methamphetamine induced psychosis patients and 197 healthy controls). The age and sex of the control subjects did not differ from those of the methamphetamine induced psychosis patients.

Results

We detected a significant association between ESR1 and methamphetamine induced psychosis patients in allele/genotype-wise analysis. For further interpretation of these associations, we performed single marker analysis of subjects divided by sex. Rs2234693 was associated with male methamphetamine induced psychosis.

Discussion

Our results suggest that rs2234693 in ESR1 may play a role in the pathophysiology of Japanese methamphetamine induced psychosis patients.     

The relationship between Bayesian motor unit number estimation and histological measurements of motor neurons in wild-type and SOD1(G93A) mice

Objective

To assess the relationship between Bayesian MUNE and histological motor neuron counts in wild-type mice and in an animal model of ALS.

Methods

We performed Bayesian MUNE paired with histological counts of motor neurons in the lumbar spinal cord of wild-type mice and transgenic SOD1^G93A mice that show progressive weakness over time. We evaluated the number of acetylcholine endplates that were innervated by a presynaptic nerve.

Results

In wild-type mice, the motor unit number in the gastrocnemius muscle estimated by Bayesian MUNE was approximately half the number of motor neurons in the region of the spinal cord that contains the cell bodies of the motor neurons supplying the hindlimb crural flexor muscles. In SOD1^G93A mice, motor neuron numbers declined over time. This was associated with motor endplate denervation at the end-stage of disease.

Conclusion

The number of motor neurons in the spinal cord of wild-type mice is proportional to the number of motor units estimated by Bayesian MUNE. In SOD1^G93A mice, there is a lower number of estimated motor units compared to the number of spinal cord motor neurons at the end-stage of disease, and this is associated with disruption of the neuromuscular junction.

Significance

Our finding that the Bayesian MUNE method gives estimates of motor unit numbers that are proportional to the numbers of motor neurons in the spinal cord supports the clinical use of Bayesian MUNE in monitoring motor unit loss in ALS patients.     

Longitudinal changes of motor cortical excitability and transcallosal inhibition after subcortical stroke

Objective

A general lack of longitudinal studies on interhemispheric interactions following stroke led us to use transcranial magnetic stimulation (TMS) to examine changes in corticospinal/intracortical excitability and transcallosal inhibition over a 1-year period following subcortical stroke.

Methods

We measured TMS parameters such as motor threshold (MT), short-interval intracortical inhibition (SICI), and ipsilateral silent period (iSP) and evaluated clinical scores at three time-points (T1, T2, and T3) in 24 patients and 25 age-matched healthy subjects.

Results

At T1, we observed reduced MTs and SICIs with prolonged iSPs in the unaffected hemisphere (UH). In contrast, increased MTs and reduced SICIs were observed in the affected hemisphere (AH). These abnormalities gradually reduced and no MEP response to TMS at T1 predicted a worse prognosis. The prolonged iSP at T1 was associated with more severe impairments, but it did not necessarily predict a worse prognosis after 1 year.

Conclusions

UH excitability was increased at the post-acute time-period, which may have resulted in enhanced transcallosal inhibition to the AH. However, it is unclear whether there was a causal relationship between the enhanced transcallosal inhibition and the extent of clinical recovery.

Significance

This is the first study to demonstrate changes in transcallosal inhibition over a longitudinal period following stroke.     

Diaphragm motor responses to phrenic nerve stimulation in ALS: Surface and needle recordings

Objective

In studies of phrenic nerve (PN) conduction in amyotrophic lateral sclerosis (ALS) both motor response amplitude and latency have been reported as abnormal. However, correlation with diaphragm motor unit loss, and with diaphragmatic function has not been fully evaluated.

Abnormalities in cortical and peripheral excitability in flail arm variant amyotrophic lateral sclerosis

Background

While some regard the flail arm syndrome as a variant of amyotrophic lateral sclerosis (ALS), others have argued that it is a distinct clinical entity. Consequently, the present study applied novel central and peripheral nerve excitability techniques to further explore disease pathophysiology in flail arm syndrome.

Methods

Cortical and peripheral nerve excitability studies were undertaken in 11 flail arm patients, defined by muscle weakness limited to the proximal aspects of the upper limbs for at least 24 months.

Results

Mean age at disease onset (60.3 years) was similar to other ALS phenotypes (58.3 years), with strong male predominance (male:female distribution: flail arm 10:1; ALS 1.5:1; p<0.05) and prolonged disease duration (flail arm 62.5 months; ALS 15.8 months; p<0.05). There was evidence of cortical hyperexcitability in flail arm patients, similar to findings in ALS, with reduction in short interval intracortical inhibition (flail arm 0.8 (0.6)%; ALS 4.1 (1.1)%; controls 8.5 (1.0)%; p<0.0001) and resting motor threshold (flail arm 53.4 (2.8)%; ALS 56.6 (1.8)%; controls 60.7 (1.5)%; p<0.05), along with an increase in motor evoked potential amplitude (flail arm 49.5 (9.0)%; ALS 44.4 (4.9)%; controls 25.8 (2.8)%; p<0.05). Peripheral nerve excitability studies demonstrated changes consistent with upregulation in persistent Na⁺ currents and reduction of slow K⁺ conductances, similar to findings in ALS.

Conclusion

This study has demonstrated the presence of cortical hyperexcitability in flail arm syndrome, along with abnormalities in peripheral nerve excitability, findings consistent with previous studies in other ALS phenotypes. By demonstrating the presence of upper motor neuron dysfunction, the present study suggests that the flail arm syndrome is an unusual variant of ALS.The “man‐in‐the barrel” syndrome is clinically characterised by severe bilateral weakness of the shoulder girdle musculature, originally reported in the setting of cerebral infarction.¹ A neurogenic variant of “man‐in‐the barrel” syndrome resulting from cervical anterior horn cell loss has been reported.^2,3 While the “man‐in‐the barrel” syndrome was first described by Vulpian,⁴ and elegantly illustrated by Gowers,⁵ later studies by Hu and colleagues² reaffirmed the original observations that this phenotype was a variant of amyotrophic lateral sclerosis (ALS).Others have argued that the neurogenic “man‐in‐the‐barrel” syndrome represents a entity distinct from ALS (brachial amyotrophic diplegia³). Indeed, the flail arm syndrome or “brachial amyotrophic diplegia” may be clinically differentiated from classic ALS by the unique pattern of muscle weakness, absence of upper motor neuron signs in the affected upper limbs and prolonged survival.^2,3The diagnosis of ALS relies on the presence of a combination of upper and lower motor neuron features with evidence of disease progression over time.⁶ Clinical evidence of upper motor neuron (UMN) dysfunction may be elusive,⁷ particularly in the early stages of ALS, or when UMN dysfunction becomes obscured by severe motor neuron loss. Given the uncertainties of the neurogenic “man‐in‐the‐barrel” syndrome, the aim of the present study was to implement novel cortical threshold tracking transcranial magnetic stimulation techniques to further explore disease pathophysiology compared with more typical ALS phenotypes.     

The ALDH2 and 5-HT2A genes interacted in bipolar-I but not bipolar-II disorder

Objective

Many physiological and pathological processes, such as infections, environmental toxins, and ionizing radiation increase bodily concentrations of oxidizing substances, known as free radicals, which lead to neurodegenerative disorders. Sleep is one of the most important factors contributing to health; however, insomnia is among the most prevalent health complaints.

Methods

In this study, for the first time in the literature, we investigated the effects of primary insomnia on certain oxidative stress biomarkers. For this purpose, glutathione peroxidase (GSH-Px), superoxide dismutase (SOD), and myeloperoxidase (MPO) activities and levels of reduced glutathione (GSH) and malondialdehyde (MDA) were measured in 30 patients with primary insomnia and 30 healthy volunteers

Results

Our results show that the patients with primary insomnia had significantly lower GSH-Px activity and higher MDA levels compared with the controls.

Conclusion

These results may indicate the important role of sleep in attenuating oxidative stress.     

Validity of multi-fiber muscle velocity recovery cycles recorded at a single site using submaximal stimuli

Objective

To examine the validity of multi-fiber muscle velocity recovery cycles (VRCs) recorded by direct muscle stimulation with submaximal stimuli.

Methods

VRCs were recorded from tibialis anterior muscle in normal volunteers with 1, 2 and 5 conditioning stimuli. Recordings were made with 6 different amplitudes of conditioning stimuli. Recordings were also made with two recording electrodes, at least 15 mm apart.

Results

Muscle VRCs in 6 subjects were not significantly different for conditioning stimuli between 80% and 150% of test stimulus amplitude. When recorded at two sites in 9 subjects, VRCs were similar when estimated over the shorter distance, the longer distance, and from the conduction time between the two electrodes.

Conclusions

Multi-fiber muscle VRCs can be reliably recorded with a single recording electrode and with equal amplitude conditioning and test stimuli.

Significance

Clinical neurophysiologists can be assured that this new method of testing muscle membrane properties provides valid and robust measurements on normal muscles.