Neurophysiological and imaging biomarkers of lower motor neuron dysfunction in motor neuron diseases/amyotrophic lateral sclerosis: IFCN handbook chapter.

This chapter discusses comprehensive neurophysiological biomarkers utilised in motor neuron disease (MND) and, in particular, its commonest form, amyotrophic lateral sclerosis (ALS). These encompass the conventional techniques including nerve conduction studies (NCS), needle and high-density surface electromyography (EMG) and H-reflex studies as well as novel techniques. In the last two decades, new methods of assessing the loss of motor units in a muscle have been developed, that are more convenient than earlier methods of motor unit number estimation (MUNE),and may use either electrical stimulation (e.g. MScanFit MUNE) or voluntary activation (MUNIX). Electrical impedance myography (EIM) is another novel approach for the evaluation that relies upon the application and measurement of high-frequency, low-intensity electrical current. Nerve excitability techniques (NET) also provide insights into the function of an axon and reflect the changes in resting membrane potential, ion channel dysfunction and the structural integrity of the axon and myelin sheath. Furthermore, imaging ultrasound techniques as well as magnetic resonance imaging are capable of detecting the constituents of morphological changes in the nerve and muscle. The chapter provides a critical description of the ability of each technique to provide neurophysiological insight into the complex pathophysiology of MND/ALS. However, it is important to recognise the strengths and limitations of each approach in order to clarify utility. These neurophysiological biomarkers have demonstrated reliability, specificity and provide additional information to validate and assess lower motor neuron dysfunction. Their use has expanded the knowledge about MND/ALS and enhanced our understanding of the relationship between motor units, axons, reflexes and other neural circuits in relation to clinical features of patients with MND/ALS at different stages of the disease. Taken together, the ultimate goal is to aid early diagnosis, distinguish potential disease mimics, monitor and stage disease progression, quantify response to treatment and develop potential therapeutic interventions.

Long-interval afferent inhibition measurement using two different methods: Normative values, repeatability and reliability.

BACKGROUND: The mechanism of Short-Latency Afferent Inhibition (SAI) is relatively well understood. In contrast, Long-Latency Afferent Inhibition (LAI) has not been as extensively studied as SAI, and its underlying mechanism remains unclear. OBJECTIVE/HYPOTHESIS: This study had two primary objectives: first, to determine the optimal ISIs for LAI measured by amplitude changes (A-LAI) using high-resolution ISI ranges; and second, to compare measurements of LAI by threshold-tracking (T-LAI). METHODS: Twenty-eight healthy volunteers (12 males aged 24- 45 years) participated in the study. Paired peripheral electrical and transcranial magnetic stimulation (TMS) stimuli (TS1mv) were applied at varying (ISIs)- 100, 200, 250, 300, 350, 400, 450, 500, 550, 600, 700, 800, 900, 1000 ms. RESULTS: Both A-LAI and T-LAI showed that LAI decreased progressively from a peak at 200 or 250 ms to 1000 ms. Using the A-LAI method, pronounced inhibition was observed at three specific ISIs: 100 ms, 250 ms and 450 ms. When A-LAI values were converted to equivalent threshold changes, they did not differ significantly from T-LAI. Reliability at distinguishing individuals, as indicated by intraclass correlation coefficient (ICC) was greater for A-LAI, with a peak value of 0.82 at 250 ms. CONCLUSION(S): The study demonstrates that ISIs of 100 ms and 250 ms can be reliably used in amplitude measurement LAI. The study demonstrates that both LAI measurements record a similar decline of inhibition with increasing ISI.

Caffeine and cortical excitability, as measured with paired-pulse transcranial magnetic stimulation.

INTRODUCTION/AIMS: The transcranial magnetic stimulation tests of short-interval intracortical inhibition (SICI) by both conventional amplitude measurements (A-SICI) and threshold-tracking (T-SICI) are important methods to investigate intracortical inhibitory circuits, and T-SICI has been proposed to aid the diagnosis of amyotrophic lateral sclerosis. Beverages containing caffeine are widely consumed, and caffeine has been reported to affect cortical excitability. The aim of this study was to determine whether these SICI tests are affected by caffeine. METHODS: Twenty-four healthy subjects (13 females, 11 males, aged from 19 to 31, mean: 26.2 ± 2.4 years) were studied in a single fixed-dose randomized double-blind placebo-controlled cross-over trial of 200 mg caffeine or placebo ingested as chewing gum. A-SICI and T-SICI, using parallel tracking (T-SICIp), were performed before and after chewing gum. RESULTS: There was no significant change in SICI parameters after placebo in A-SICI (p > .10) or T-SICIp (p > .30), and no significant effect of caffeine was found on A-SICI (p > .10) or T-SICIp (p > .50) for any of the interstimulus intervals. DISCUSSION: There is no need for caffeine abstention before measurements of SICI by either the T-SICI or A-SICI measurements.

Three different short-interval intracortical inhibition methods in early diagnosis of amyotrophic lateral sclerosis.

Objectives: To compare the utility of conventional amplitude measurements of short-interval intracortical inhibition (A-SICI) with two threshold-tracking (T-SICI) methods, as aids to early diagnosis of amyotrophic lateral sclerosis (ALS). The new parallel threshold-tracking method (T-SICIp) was compared with the previously used serial tracking method (T-SICIs). Methods: 112 consecutive patients referred with the suspicion of ALS and 40 healthy controls were prospectively included. Based on clinical follow-up, patients were divided into 67 patients with motor neuron disease (MND) comprising progressive muscular atrophy (PMA) as well as ALS, and 45 patient controls. SICI was recorded from first dorsal interosseus muscle using the three different protocols. Results: MND patients had significantly reduced T-SICIp, T-SICIs and A-SICI, compared with healthy controls and patient controls, while healthy and patient controls were similar. Paradoxically, T-SICIp was least affected in MND patients with the most upper motor neuron (UMN) signs (Spearman ρ = 0.537, P < 0.0001) whereas there was no correlation for T-SICIs or A-SICI. T-SICIp also provided the best discrimination between patient controls and MND as determined by the receiver operating characteristic (ROC) curves. For patients with no UMN signs, area under ROC curve for 2-3ms inter-stimulus intervals was 0.931 for T-SICIp, 0.771 for T-SICIs and 0.786 for A-SICI. Conclusions: SICI is a sensitive measure for detection of cortical involvement in ALS patients. T-SICIp has higher sensitivity and specificity than T-SICIs and A-SICI, particularly in patients without any upper motor neuron signs.

Differences in nerve excitability properties across upper limb sensory and motor axons.

OBJECTIVE: The excitability of motor and sensory axons of the main upper limb nerves were compared to characterise the differences between nerves and provide a guide for future studies in human diseases with median neuropathy at the wrist. METHODS: Axonal excitability studies were undertaken on median and ulnar motor (APB and ADM) and sensory axons (D2 and D5) and the superficial radial axons (D1) using a threshold tracking technique. RESULTS: Compared to the median, ulnar motor axons had reduced early depolarising threshold electrotonus (TEd40(10-20 ms) p = 0.02) and superexcitability (p = 0.03). The ulnar sensory axons required a stronger stimulus (p = 0.02) and had a larger rheobase (p = 0.02) than median axons, but were otherwise comparable. The superficial radial axons were "fanned-in" compared to median, and to a lesser degree ulnar axons, with greater resting I/V slope. Mathematical modelling of the radial and median sensory axons suggested that a 15.1% reduction in conductances between nodal and internodal compartments accounted for 82% of this discrepancy. CONCLUSIONS: The excitability parameters of motor and sensory axons are most comparable between median and ulnar nerves. SIGNIFICANCE: The present study demonstrates the feasibility of, and provides normative data for, axonal excitability recordings of the radial and ulnar nerves. We suggest the use of ulnar recordings as an alternative to the median nerve in the setting of compressive neuropathy at the wrist.

Short latency afferent inhibition: comparison between threshold-tracking and conventional amplitude recording methods.

Short-latency afferent inhibition (SAI), which is conventionally measured as a reduction in motor evoked potential amplitude (A-SAI), is of clinical interest as a potential biomarker for cognitive impairment. Since threshold-tracking has some advantages for clinical studies of short-interval cortical inhibition, we have compared A-SAI with a threshold-tracking alternative method (T-SAI). In the T-SAI method, inhibition was calculated by tracking the required TMS intensity for the targeted MEP amplitude (200 uV) both for the test (TMS only) and paired (TMS and peripheral stimulation) stimuli. A-SAI and T-SAI were recorded from 31 healthy subjects using ten stimuli at each of 12 inter-stimulus intervals, once in the morning and again in the afternoon. There were no differences between morning and afternoon recordings. When A-SAI was normalized by log conversion it was closely related to T-SAI. Between subjects, variability was similar for the two techniques, but within-subject variability was significantly smaller for normalized A-SAI. Conventional amplitude measurements appear more sensitive for detecting changes within-subjects, such as in interventional studies, but threshold-tracking may be as sensitive as detecting abnormal SAI in a patient.

Short interval intracortical inhibition: Variability of amplitude and threshold-tracking measurements with 6 or 10 stimuli per point.

Reduced short-interval intracortical inhibition (SICI) in motor neuron disease has been demonstrated by amplitude changes (A-SICI) and threshold-tracking (T-SICI) using 10 stimuli per inter-stimulus interval (ISI). To test whether fewer stimuli would suffice, A-SICI and T-SICI were recorded twice from 30 healthy subjects using 6 and 10 stimuli per ISI. Using fewer stimuli increased mean A-SICI variances by 23.8% but the 7.3% increase in T-SICI variance was not significant. We conclude that our new parallel threshold-tracking SICI protocol, with 6 stimuli per ISI, can reduce time and stimulus numbers by 40% without appreciable loss of accuracy.

Axonal excitability changes in children with spinal muscular atrophy treated with nusinersen.

Spinal muscular atrophy (SMA) is associated with developmental disruption of motor axons in ventral roots of the spinal cord alongside motor axon degeneration. The pathogenesis of peripheral axonal change during development is pertinent to understand treatment response. Nerve excitability techniques, stimulating the median motor nerve at the wrist, were utilised to investigate axonal change during neurodevelopment in 24 children with SMA, compared with 71 age-matched controls. Longitudinal axonal response to nusinersen treatment in 18 children was also investigated. Significant differences in axonal development were noted in the youngest children with SMA, signified by reduced compound muscle action potential (CMAP) (P = 0.030), higher axonal threshold (P = 0.016), rheobase (minimal current amplitude of infinite duration, required to generate an action potential) (P = 0.012) and greater changes in depolarising and hyperpolarising threshold electrotonus. Subexcitability increased in all children with SMA, compared to controls. With treatment, nerve excitability changes were observed prominently in young children, with increases in CMAP, reduction in axonal threshold, fanning-in of threshold electrotonus, increase in resting current-threshold slope and reduction in subexcitability. Whilst motor axons continue to mature in SMA, developmental delays in passive and active membrane properties occur especially in early childhood. Concurrently, motor axons actively undergo degeneration. Nusinersen restores the developmental trajectory of motor axons reducing degeneration, especially in children with early treatment initiation. Our findings move the field forward in understanding the developmental aspect of childhood-onset motor neurone diseases and changes in axonal function associated with disease modification. KEY POINTS: Pathomechanisms in spinal muscular atrophy involve concurrent neurodevelopmental and neurodegenerative processes. The greatest delays in maturation of the passive and active properties of the peripheral motor axon are seen in early childhood. Nusinersen facilitates developmental recovery of the motor axon whilst also reducing neurodegeneration. Axonal dysfunction is reversed with SMN repletion particularly when intervention occurs early in development.

Conventional and Threshold-Tracking Transcranial Magnetic Stimulation Tests for Single-handed Operation.

Most single-pulse transcranial magnetic stimulation (TMS) parameters (e.g., motor threshold, stimulus-response function, cortical silent period) are used to examine corticospinal excitability. Paired-pulse TMS paradigms (e.g., short- and long-interval intracortical inhibition (SICI/LICI), short-interval intracortical facilitation (SICF), and short- and long-latency afferent inhibition (SAI/LAI)) provide information about intracortical inhibitory and facilitatory networks. This has long been done by the conventional TMS method of measuring changes in the size of the motor-evoked potentials (MEPs) in response to stimuli of constant intensity. An alternative threshold-tracking approach has recently been introduced whereby the stimulus intensity for a target amplitude is tracked. The diagnostic utility of threshold-tracking SICI in amyotrophic lateral sclerosis (ALS) has been shown in previous studies. However, threshold-tracking TMS has only been used in a few centers, in part due to the lack of readily available software but also perhaps due to uncertainty over its relationship to conventional single- and paired-pulse TMS measurements. A menu-driven suite of semi-automatic programs has been developed to facilitate the broader use of threshold-tracking TMS techniques and to enable direct comparisons with conventional amplitude measurements. These have been designed to control three types of magnetic stimulators and allow recording by a single operator of the common single- and paired-pulse TMS protocols. This paper shows how to record a number of single- and paired-pulse TMS protocols on healthy subjects and analyze the recordings. These TMS protocols are fast and easy to perform and can provide useful biomarkers in different neurological disorders, particularly neurodegenerative diseases such as ALS.

Early diagnosis of amyotrophic lateral sclerosis by threshold tracking and conventional transcranial magnetic stimulation.

BACKGROUND AND PURPOSE: Short-interval intracortical inhibition by threshold tracking (T-SICI) has been proposed as a diagnostic tool for amyotrophic lateral sclerosis (ALS) but has not been compared directly with conventional amplitude measurements (A-SICI). This study compared A-SICI and T-SICI for sensitivity and clinical usefulness as biomarkers for ALS. METHODS: In all, 104 consecutive patients referred with suspicion of ALS were prospectively included and were subsequently divided into 62 patients with motor neuron disease (MND) and 42 patient controls (ALS mimics) by clinical follow-up. T-SICI and A-SICI recorded in the first dorsal interosseus muscle (index test) were compared with recordings from 53 age-matched healthy controls. The reference standard was the Awaji criteria. Clinical scorings, conventional nerve conduction studies and electromyography were also performed on the patients. RESULTS: Motor neuron disease patients had significantly reduced T-SICI and A-SICI compared with the healthy and patient control groups, which were similar. Sensitivity and specificity for discriminating MND patients from patient controls were high (areas under the receiver operating characteristic curves 0.762 and 0.810 for T-SICI and A-SICI respectively at 1-3.5 ms). Paradoxically, T-SICI was most reduced in MND patients with the fewest upper motor neuron (UMN) signs (Spearman ρ = 0.565, p = 4.3 × 10-6 ). CONCLUSIONS: Amplitude-based measure of cortical inhibition and T-SICI are both sensitive measures for the detection of cortical involvement in MND patients and may help early diagnosis of ALS, with T-SICI most abnormal before UMN signs have developed. The gradation in T-SICI from pathological facilitation in patients with minimal UMN signs to inhibition in those with the most UMN signs may be due to progressive degeneration of the subset of UMNs experiencing facilitation.

Motor cortical excitability predicts cognitive phenotypes in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are well-recognised as an extended disease spectrum. This study hypothesised that cortical hyperexcitability, an early pathophysiological abnormality in ALS, would distinguish cognitive phenotypes, as a surrogate marker of pathological disease burden. 61 patients with ALS, matched for disease duration (pure motor ALS, n = 39; ALS with coexistent FTD, ALS-FTD, n = 12; ALS with cognitive/behavioural abnormalities not meeting FTD criteria, ALS-Cog, n = 10) and 30 age-matched healthy controls. Cognitive function on the Addenbrooke's cognitive examination (ACE) scale, behavioural function on the motor neuron disease behavior scale (MiND-B) and cortical excitability using transcranial magnetic stimulation (TMS) were documented. Cortical resting motor threshold (RMT), lower threshold indicating hyperexcitability, was lower in ALS-FTD (50.2 ± 6.9) compared to controls (64.3 ± 12.6, p < 0.005), while ALS-Cog (63.3 ± 12.7) and ALS (60.8 ± 13.9, not significant) were similar to controls. Short interval intracortical inhibition (SICI) was reduced across all ALS groups compared to controls, indicating hyperexcitability. On receiver operating characteristic curve analysis, RMT differentiated ALS-FTD from ALS (area under the curve AUC = 0.745, p = 0.011). The present study has identified a distinct pattern of cortical excitability across cognitive phenotypes in ALS. As such, assessment of cortical physiology may provide more precise clinical prognostication in ALS.

Comparison of figure-of-8 and circular coils for threshold tracking transcranial magnetic stimulation measurements.

OBJECTIVES: The transcranial magnetic stimulation (TMS) technique of threshold-tracking short-interval intracortical inhibition (T-SICI) has been proposed as a diagnostic tool for amyotrophic lateral sclerosis (ALS). Most of these studies have used a circular coil, whereas a figure-of-8 coil is usually recommended for paired-pulse TMS measurements. The aim of this study was to compare figure-of-8 and circular coils for T-SICI in the upper limb, with special attention to reproducibility, and the pain or discomfort experienced by the subjects. METHODS: Twenty healthy subjects (aged: 45.5 ±â€¯6.7, mean ±â€¯SD, 9 females, 11 males) underwent two examinations with each coil, in morning and afternoon sessions on the same day, with T-SICI measured at interstimulus intervals (ISIs) from 1-7 ms. After each examination the subjects rated degree of pain/discomfort from 0 to 10 using a numerical rating scale (NRS). RESULTS: Mean T-SICI was higher for the figure-of-8 than for the circular coil at ISI of 2 ms (p < 0.05) but did not differ at other ISIs. Intra-subject variability did not differ between coils, but mean inhibition from 1-3.5 ms was less variable between subjects with the figure-of-8 coil (SD 7.2% vs. 11.2% RMT, p < 0.05), and no such recordings were without inhibition (vs. 6 with the circular coil). The subjects experienced less pain/discomfort with the figure-of-8 coil (mean NRS: 1.9 ±â€¯1.28 vs 2.8 ±â€¯1.60, p < 0.005). DISCUSSION: The figure-of-8 coil may have better applicability in patients, due to the lower incidence of lack of inhibition in healthy subjects, and the lower experience of pain or discomfort.

Electrophysiological investigation of motor axonal excitability in a mouse model of nerve constriction injury.

Peripheral nerve injuries caused by focal constriction are characterised by local nerve ischaemia, axonal degeneration, demyelination, and neuroinflammation. The aim of this study was to understand temporal changes in the excitability properties of injured motor axons in a mouse model of nerve constriction injury (NCI). The excitability of motor axons following unilateral sciatic NCI was studied in male C57BL/6J mice distal to the site of injury at the acute (6 hours-1 week) and chronic (up to 20 weeks) phases of injury, using threshold tracking. Multiple measures of nerve excitability, including strength-duration properties, threshold electrotonus, current-threshold relationship, and recovery cycle were examined using the automated nerve excitability protocol (TRONDNF). Acutely, injured motor axons developed a pattern of excitability characteristic of ischemic depolarisation. In most cases, the sciatic nerve became transiently inexcitable. When a liminal compound muscle action potential could again be recorded, it had an increase in threshold and latency, compared to both pre-injury baseline and sham-injured groups. These axons showed a greater threshold change in response to hyperpolarising threshold electrotonus and a significant upward shift in the recovery cycle. Mathematical modelling suggested that the changes seen in chronically injured axons involve shortened internodes, reduced myelination, and exposed juxtaparanodal fast K+ conductances. The findings of this study demonstrate long-term changes in motor excitability following NCI (involving alterations in axonal properties and ion channel activity) and are important for understanding the mechanisms of neurapraxic injuries and traumatic mononeuropathies.

Short-interval intracortical inhibition as a function of inter-stimulus interval: Three methods compared.

BACKGROUND: Short-interval intracortical inhibition (SICI), as measured by threshold-tracking as a function of inter-stimulus interval (ISI), has been proposed as a useful biomarker for amyotrophic lateral sclerosis (ALS), but its relationship to conventional amplitude measurements has not been established. METHODS: Serial tracking of SICI at increasing ISIs from 1 to 7 ms (T-SICIs) was compared in 50 healthy control subjects with the same ISIs tracked in parallel (T-SICIp), and with conventional amplitude measurements (A-SICI). For T-SICIp and A-SICI, pairs of conditioning and test stimuli with different ISIs were pseudo-randomised and interspersed with test-alone stimuli given at regular intervals. Thresholds were estimated by regression of log peak-to-peak amplitude on stimulus. RESULTS: T-SICIp and A-SICI were closely related: a ten-fold reduction in amplitude corresponding to an approximately 18% increase in threshold. Threshold increases were greater for T-SICIs than for T-SICIp at 3.5-5 ms (P < 0.001). This divergence depended on the initial settings and whether ISIs were progressively increased or decreased, and was attributed to the limitations of the serial tracking protocol. SICI variability between subjects was greatest for T-SICIs estimates and least for A-SICI, and only A-SICI estimates revealed a significant decline in inhibition with age. CONCLUSIONS: The serial tracking protocol did not accurately show the dependence of inhibition on ISI. Randomising ISIs gives corresponding SICI measures, whether tracking thresholds or measuring amplitude measurements. SICI variability suggested that A-SICI measurements may be the most sensitive to loss of inhibition.

Motor unit changes in children with symptomatic spinal muscular atrophy treated with nusinersen.

OBJECTIVES: To elucidate the motor unit response to intrathecal nusinersen in children with symptomatic spinal muscular atrophy (SMA) using a novel motor unit number estimation technique. METHODS: MScanFit MUNE studies were sequentially undertaken from the abductor pollicis brevis muscle after stimulation of the median nerve in a prospective cohort of symptomatic children with SMA, undergoing intrathecal treatment with nusinersen at a single neuromuscular centre from June 2017 to August 2019. Electrophysiological measures included compound muscle action potential (CMAP), motor unit number estimation (MUNE), motor unit number contributing to 50%-100% of CMAP (N50) and measures of collateral reinnervation including largest single motor unit potential (LSMUP) and amplitude of the smallest unit contributing to N50 (A50). RESULTS: Twenty children (median age 99 months, range 4-193) were followed for a median of 13.8 (4-33.5) months. Therapeutic intervention was an independent and significant contributor to an increase in CMAP (p = 0.005), MUNE (p = 0.001) and N50 (p = 0.04). The magnitude of this electrophysiological response was increased in children with shorter disease durations (p<0.05). Electrophysiological changes delineated children who were functionally stable from those who attained clinically significant gains in motor function. INTERPRETATION: Nusinersen therapy facilitated functional innervation in SMA through recovery of smaller motor units. Delineation of biomechanisms of therapeutic response may be the first step in identifying potential novel targets for disease modification in this and other motor neuropathies. MScanFit MUNE techniques may have a broader role in establishing biomarkers of therapeutic response in similar adult-onset diseases.

Neuropathy in sporadic inclusion body myositis: A multi-modality neurophysiological study.

OBJECTIVE: Sporadic inclusion body myositis (sIBM) has been associated with neuropathy. This study employs nerve excitability studies to re-examine this association and attempt to understand underlying pathophysiological mechanisms. METHODS: Twenty patients with sIBM underwent median nerve motor and sensory excitability studies, clinical assessments, conventional nerve conduction testing (NCS) and quantitative thermal threshold studies. These results were compared to established normal controls, or results from a normal cohort of older control individuals. RESULTS: Seven sIBM patients (35%) demonstrated abnormalities in conventional NCS, with ten patients (50%) demonstrating abnormalities in thermal thresholds. Median nerve motor and sensory excitability differed significantly in sIBM patients when compared to normal controls. None of these neurophysiological markers correlated significantly with clinical markers of sIBM severity. CONCLUSION: A concurrent neuropathy exists in a significant proportion of sIBM patients, with nerve excitability studies revealing changes possibly consistent with axolemmal depolarization or concurrent neuronal adaptation to myopathy. Neuropathy in sIBM does not correlate with muscle disease severity and may reflect a differing tissue response to a common pathogenic factor. SIGNIFICANCE: This study affirms the presence of a concurrent neuropathy in a large proportion of sIBM patients that appears independent of the severity of myopathy.

Acute changes in nerve excitability following oxaliplatin treatment in mice.

Oxaliplatin chemotherapy produces acute changes in peripheral nerve excitability in humans by modulating voltage-gated Na+ channel activity. However, there are few animal studies of oxaliplatin-induced neuropathy that demonstrate similar changes in excitability. In the present study, we measured the excitability of motor and sensory caudal nerve in C57BL/6 mice after oxaliplatin injections either systemically (intraperitoneal) or locally (intramuscular at the base of the tail). As opposed to intraperitoneal administration of oxaliplatin, a single intramuscular injection of oxaliplatin produced changes in both motor and sensory axons. In motor axons, oxaliplatin caused a greater change in response to long-lasting depolarization and an upward shift in the recovery cycle, particularly at 24 h [depolarizing threshold electrotonus (TEd) 10-20 ms, P = 0.0095; TEd 90-100 ms, P = 0.0056) and 48 h (TEd 10-20 ms, P = 0.02; TEd 90-100 ms, P = 0.04) posttreatment. Oxaliplatin treatment also stimulated the production of afterdischarges in motor axons. These changes were transient and showed dose dependence. Mathematical modeling demonstrated that these changes could be accounted for by slowing inactivation of voltage-gated Na+ channels by 73.3% and reducing fast K+ conductance by 47% in motor axons. In sensory axons, oxaliplatin caused an increase in threshold, a reduction in peak amplitude, and greater threshold changes to strong hyperpolarizing currents on days 4 and 8. Thus, local administration of oxaliplatin produced clinically relevant changes in nerve excitability in mice and may provide an alternative approach for the study of acute oxaliplatin-induced neurotoxicity.NEW & NOTEWORTHY We present a novel mouse model of acute oxaliplatin-induced peripheral neurotoxicity that is comparable to clinical observations. Intramuscular injection of oxaliplatin produced acute changes in motor nerve excitability that were attributable to alterations in Na+ and K+ channel activity. Conversely, we were unable to show any significant changes in nerve excitability with systemic intraperitoneal injections of oxaliplatin. This study suggests that local intramuscular injection is a valid approach for modelling oxaliplatin-induced peripheral neuropathy in animals.

Interrogating interneurone function using threshold tracking of the H reflex in healthy subjects and patients with motor neurone disease.

OBJECTIVE: The excitability of the lower motoneurone pool is traditionally tested using the H reflex and a constant-stimulus paradigm, which measures changes in the amplitude of the reflex response. This technique has limitations because reflex responses of different size must involve the recruitment or inhibition of different motoneurones. The threshold-tracking technique ensures that the changes in excitability occur for an identical population of motoneurones. We aimed to assess this technique and then apply it in patients with motor neurone disease (MND). METHODS: The threshold-tracking approach was assessed in 17 healthy subjects and 11 patients with MND. The soleus H reflex was conditioned by deep peroneal nerve stimulation producing reciprocal Ia and so-called D1 and D2 inhibitions, which are believed to reflect presynaptic inhibition of soleus Ia afferents. RESULTS: Threshold tracking was quicker than the constant-stimulus technique and reliable, properties that may be advantageous for clinical studies. D1 inhibition was significantly reduced in patients with MND. CONCLUSIONS: Threshold tracking is useful and may be preferable under some conditions for studying the excitability of the motoneurone pool. The decreased D1 inhibition in the patients suggests that presynaptic inhibition may be reduced in MND. SIGNIFICANCE: Reduced presynaptic inhibition could be evidence of an interneuronopathy in MND. It is possible that the hyperreflexia is a spinal pre-motoneuronal disorder, and not definitive evidence of corticospinal involvement in MND.

Early focality and spread of cortical dysfunction in amyotrophic lateral sclerosis: A regional study across the motor cortices.

OBJECTIVE: To characterise the regional cortical patterns underlying clinical symptomatology in amyotrophic lateral sclerosis (ALS). METHODS: 138 patients prospectively underwent transcranial magnetic stimulation studies from hand and leg cortical regions of each hemisphere, obtaining motor evoked potentials from all four limbs. Patients were categorised by clinical phenotype and underwent clinical and peripheral evaluation of disease. RESULTS: Cortical dysfunction was evident across the motor cortices, with reduction in short-interval intracortical inhibition (SICI) suggesting the presence of widespread cortical hyperexcitability, most prominently from clinically affected regions (hand p < 0.0001; leg p < 0.01). In early disease, cortical abnormalities were asymmetric between hemispheres, focally corresponding to clinical site-of-onset (p < 0.05). Degrees of cortical dysfunction varied between phenotypes, with the bulbar-onset cohort demonstrating greatest reduction in SICI (p = 0.03). CONCLUSIONS: The pattern of cortical dysfunction appears linked to clinical evolution in ALS, with early focal asymmetry preceding widespread changes in later disease. Cortical differences across phenotypes may influence clinical variability. SIGNIFICANCE: This is the first study to extensively map cortical abnormalities from multiple motor regions across hemispheres. The early cortical signature mirrors symptom laterality, supporting a discrete region of disease onset. Phenotypes appear to exist within a pathophysiological continuum, but cortical heterogeneity may mediate observed differences in clinical outcome.

The effect of coil type and limb dominance in the assessment of lower-limb motor cortex excitability using TMS.

PURPOSE: Clinical application of transcranial magnetic stimulation (TMS) has rapidly increased but the majority of studies have targeted upper limb muscles, with few exploring the lower-limb. Differences of coil choice have added to methodological difficulties of lower-limb studies and have challenged consistent interpretation of these parameters. The aims of this study were to determine the optimal coil choice for assessing lower-limb cortical excitability and assess laterality of normal cortical function. METHODS: 69 recordings were undertaken from the tibialis anterior muscle from 48 healthy participants. Three coil types currently used in lower-limb studies (90 mm circular; 70 mm figure-of-8; and 110 mm double cone) were explored using single pulse TMS and paired-pulse threshold tracking TMS (TT-TMS) paradigms, with peripheral function also assessed. Cortical symmetry was ascertained with bilateral recordings (dominant versus non-dominant muscles). RESULTS: The double-cone coil showed greatest efficacy, with significantly lower resting motor thresholds (49.0 ± 2.3%, p<0.0005) and greater intracortical facilitation compared to the alternate coil choices. Using the double-cone coil, paired-pulse TT-TMS generated an averaged short interval intracortical inhibition of 11.3 ± 1.2%, with an averaged intracortical facilitation of -6.1 ± 1.9%. There were no differences between dominant and non-dominant hemispheres. CONCLUSIONS: The present study identified key differences in cortical parameters between the currently utilised coils for lower-limb TMS. Specifically, this indicates the importance of standardizing the lower-limb TMS protocol, particularly for accurate interpretation in disease pathology.