Hyperexcitability In Amyotrophic Lateral Sclerosis Research Articles

Reduction in short interval intracortical inhibition from the early stage reflects the pathophysiology in amyotrophic lateral sclerosis: A meta-analysis study.

Cortical hyperexcitability has been identified as a diagnostic and pathogenic biomarker of amyotrophic lateral sclerosis (ALS). Cortical excitability is assessed by transcranial magnetic stimulation (TMS), a non-invasive neurophysiological technique. The TMS biomarkers exhibiting highest sensitivity for cortical hyperexcitability in ALS remain to be elucidated. A meta-analysis was performed to determine the TMS biomarkers exhibiting the highest sensitivity for cortical hyperexcitability in ALS. A systematic literature review was conducted of all relevant studies published in the English language by searching PubMed, MEDLINE, Embase and Scopus electronic databases from 1 January 2006 to 28 February 2023. Inclusion criteria included studies reporting the utility of threshold tracking TMS (serial ascending method) in ALS and controls. In total, more than 2500 participants, incorporating 1530 ALS patients and 1102 controls (healthy, 907; neuromuscular, 195) were assessed with threshold tracking TMS across 25 studies. Significant reduction of mean short interval intracortical inhibition (interstimulus interval 1-7 ms) exhibited the highest standardized mean difference with moderate heterogeneity (-0.994, 95% confidence interval -1.12 to -0.873, p < 0.001; Q = 38.61, p < 0.05; I2 = 40%). The reduction of cortical silent period duration along with an increase in motor evoked potential amplitude and intracortical facilitation also exhibited significant, albeit smaller, standardized mean differences. This large meta-analysis study disclosed that mean short interval intracortical inhibition reduction exhibited the highest sensitivity for cortical hyperexcitability in ALS. Combined findings from this meta-analysis suggest that research strategies aimed at understanding the cause of inhibitory interneuronal circuit dysfunction could enhance understanding of ALS pathogenesis.

Distinct neuronal circuits mediate cortical hyperexcitability in amyotrophic lateral sclerosis.

Cortical hyperexcitability is an important pathophysiological mechanism in amyotrophic lateral sclerosis (ALS), reflecting a complex interaction of inhibitory and facilitatory interneuronal processes that evolves in the degenerating brain. The advances in physiological techniques have made it possible to interrogate progressive changes in the motor cortex. Specifically, the direction of transcranial magnetic stimulation (TMS) stimulus within the primary motor cortex can be utilised to influence descending corticospinal volleys and to thereby provide information about distinct interneuronal circuits. Cortical motor function and cognition was assessed in 29 ALS patients with results compared to healthy volunteers. Cortical dysfunction was assessed using threshold-tracking TMS to explore alterations in short interval intracortical inhibition (SICI), short interval intracortical facilitation (SICF), the index of excitation (IE), and stimulus response (SR) curves using a figure-of-eight coil with the coil oriented relative to the primary motor cortex in a posterior-anterior (PA), lateral-medial (LM), and anterior-posterior (AP) direction. Mean SICI, between interstimulus interval (ISI) of 1-to-7 ms, was significantly reduced in ALS patients compared to healthy controls when assessed with the coil oriented in PA (P = 0.044) and LM (P = 0.005) but not the AP (P = 0.08) directions. A significant correlation between mean SICI oriented in a PA direction and the total Edinburgh Cognitive and Behavioural ALS Screen score (Rho = 0.389, P = 0.037) was evident. In addition, the mean SICF, between ISI 1-to-5 ms, was significantly increased in ALS patients when recorded with TMS coil oriented in PA (P = 0.035) and LM (P < 0.001) directions. In contrast, SICF recorded with TMS coil oriented in the AP direction was comparable between ALS and controls (P = 0.482). The IE was significantly increased in ALS patients when recorded with the TMS coil oriented in PA (P = 0.041) and LM (P = 0.003) directions. In ALS patients, a significant increase in the SR curve gradient was evident compared to controls when recorded with TMS coil oriented in PA (P < 0.001), LM (P < 0.001) and AP (P = 0.002) directions. The present study has established that dysfunction of distinct interneuronal circuits mediates the development of cortical hyperexcitability in ALS. Specifically, complex interplay between inhibitory circuits and facilitatory interneuronal populations, that are preferentially activated by stimulation in posterior-to-anterior or lateral-to-medial directions, promotes cortical hyperexcitability in ALS. Mechanisms that underlie dysfunction of these specific cortical neuronal circuits will enhance understanding of the pathophysiological processes in ALS, with the potential to uncover focussed therapeutic targets.

Cortical hyperexcitability in amyotrophic lateral sclerosis: from pathogenesis to diagnosis.

Identification of upper motor neuron involvement remains a critical component of a diagnosis of amyotrophic lateral sclerosis (ALS), although supportive clinical signs are often not easily appreciated, particularly in the early symptomatic stages of the disease. Although diagnostic criteria have been developed to facilitate improved detection of lower motor neuron impairment through electrophysiological features that have improved diagnostic sensitivity, assessment of upper motor neuron involvement remains problematic. Recent evidence has emerged about pathophysiological processes, particularly glutamate-mediated excitotoxicity, which has resulted in the development of novel diagnostic investigations and uncovered potential therapeutic targets. Advances in genetics, including the C9orf72 gene, have changed concepts of ALS, from being classified as a neuromuscular disease to a disease that forms a continuum with other primary neurodegenerative disorders, particularly frontotemporal dementia. Transcranial magnetic stimulation has been utilized to provide pathophysiological insights, leading to the development of diagnostic and therapeutic biomarkers, which are now being introduced into the clinical setting. Specifically, the advent of cortical hyperexcitability has been consistently identified as an early and intrinsic feature of ALS. With greater accessibility of TMS techniques promoting clinical utilization, TMS measures of cortical function may develop as a diagnostic biomarker, with further potential utility in the clinical trial setting for monitoring of neuroprotective and genetic-based therapies.

Relationship between motor cortical and peripheral axonal hyperexcitability in amyotrophic lateral sclerosis

BackgroundPrevious studies have shown that patients with amyotrophic lateral sclerosis (ALS) have hyperexcitability in both the motor cortex and peripheral motor axons, but the relationship between central and peripheral excitability...

Poly-dipeptides produced from C9orf72 hexanucleotide repeats cause selective motor neuron hyperexcitability in ALS

SignificanceThe GGGGCC hexanucleotide repeat expansion in the chromosome 9 open reading frame 72 (C9orf72) gene is the most common genetic cause of amyotrophic lateral sclerosis (ALS). Despite myriad studies on the toxic effects of poly-dipeptides produced from the C9orf72 repeats, the mechanisms underlying the selective hyperexcitability of motor cortex that characterizes the early stages of C9orf72 ALS patients remain elusive. Here, we show that the proline-arginine poly-dipeptides cause hyperexcitability in cortical motor neurons by increasing persistent sodium currents conducted by the Nav1.2/β4 sodium channel complex, which is highly expressed in the motor cortex. These findings provide the basis for understanding how the C9orf72 mutation causes motor neuron hyperactivation that can lead to the motor neuron death in C9orf72 ALS.

Cortical hyperexcitability: Diagnostic and pathogenic biomarker of ALS

Cortical hyperexcitability is an early and intrinsic feature of both sporadic and familial forms of amyotrophic lateral sclerosis (ALS).. Importantly, cortical hyperexcitability appears to be associated with motor neuron degeneration, possibly via an anterograde glutamate-mediated excitotoxic process, thereby forming a pathogenic basis for ALS. The presence of cortical hyperexcitability in ALS patients may be readily determined by transcranial magnetic stimulation (TMS), a neurophysiological tool that provides a non-invasive and painless method for assessing cortical function. Utilising the threshold tracking TMS technique, cortical hyperexcitability has been established as a robust diagnostic biomarker that distinguished ALS from mimicking disorders at early stages of the disease process. The present review discusses the pathophysiological and diagnostic utility of cortical hyperexcitability in ALS.

Neurophysiological Mechanisms Underlying Cortical Hyper-Excitability in Amyotrophic Lateral Sclerosis: A Review.

Amyotrophic lateral sclerosis (ALS) is a progressive neuromotor disease characterized by the loss of upper and lower motor neurons (MNs), resulting in muscle paralysis and death. Early cortical hyper-excitability is a common pathological process observed clinically and in animal disease models. Although the mechanisms that underlie cortical hyper-excitability are not completely understood, the molecular and cellular mechanisms that cause enhanced neuronal intrinsic excitability and changes in excitatory and inhibitory synaptic activity are starting to emerge. Here, we review the evidence for an anterograde glutamatergic excitotoxic process, leading to cortical hyper-excitability via intrinsic cellular and synaptic mechanisms and for the role of interneurons in establishing disinhibition in clinical and experimental settings. Understanding the mechanisms that lead to these complex pathological processes will likely produce key insights towards developing novel therapeutic strategies to rescue upper MNs, thus alleviating the impact of this fatal disease.

Cortical Circuit Dysfunction as a Potential Driver of Amyotrophic Lateral Sclerosis.

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease that affects selected cortical and spinal neuronal populations, leading to progressive paralysis and death. A growing body of evidences suggests that the disease may originate in the cerebral cortex and propagate in a corticofugal manner. In particular, transcranial magnetic stimulation studies revealed that ALS patients present with early cortical hyperexcitability arising from a combination of increased excitability and decreased inhibition. Here, we discuss the possibility that initial cortical circuit dysfunction might act as the main driver of ALS onset and progression, and review recent functional, imaging and transcriptomic studies conducted on ALS patients, along with electrophysiological, pathological and transcriptomic studies on animal and cellular models of the disease, in order to evaluate the potential cellular and molecular origins of cortical hyperexcitability in ALS.

Fasciculations demonstrate daytime consistency in amyotrophic lateral sclerosis.

Fasciculations represent early neuronal hyperexcitability in amyotrophic lateral sclerosis (ALS). To aid calibration as a disease biomarker, we set out to characterize the daytime variability of fasciculation firing. Fasciculation awareness scores were compiled from 19 ALS patients. In addition, 10 ALS patients prospectively underwent high-density surface electromyographic (HDSEMG) recordings from biceps and gastrocnemius at three time-points during a single day. Daytime fasciculation awareness scores were low (mean: 0.28 muscle groups), demonstrating significant variability (coefficient of variation: 303%). Biceps HDSEMG recordings were highly consistent for fasciculation potential frequency (intraclass correlation coefficient [ICC] = 95%, n = 19) and the interquartile range of fasciculation potential amplitude (ICC = 95%, n = 19). These parameters exhibited robustness to observed fluctuations in data quality parameters. Gastrocnemius demonstrated more modest levels of consistency overall (44% to 62%, n = 20). There was remarkable daytime consistency of fasciculation firing in the biceps of ALS patients, despite sparse and intermittent awareness among patients' accounts.

Dynamic interplay between H-current and M-current controls motoneuron hyperexcitability in amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a type of motor neuron disease (MND) in which humans lose motor functions due to progressive loss of motoneurons in the cortex, brainstem, and spinal cord. In patients and in animal models of MND it has been observed that there is a change in the properties of motoneurons, termed neuronal hyperexcitability, which is an exaggerated response of the neurons to a stimulus. Previous studies suggested neuronal excitability is one of the leading causes for neuronal loss, however the factors that instigate excitability in neurons over the course of disease onset and progression are not well understood, as these studies have looked mainly at embryonic or early postnatal stages (pre-symptomatic). As hyperexcitability is not a static phenomenon, the aim of this study was to assess the overall excitability of upper motoneurons during disease progression, specifically focusing on their oscillatory behavior and capabilities to fire repetitively. Our results suggest that increases in the intrinsic excitability of motoneurons are a global phenomenon of aging, however the cellular mechanisms that underlie this hyperexcitability are distinct in SOD1G93A ALS mice compared with wild-type controls. The ionic mechanism driving increased excitability involves alterations of the expression levels of HCN and KCNQ channel genes leading to a complex dynamic of H-current and M-current activation. Moreover, we show a negative correlation between the disease onset and disease progression, which correlates with a decrease in the expression level of HCN and KCNQ channels. These findings provide a potential explanation for the increased vulnerability of motoneurons to ALS with aging.

Imbalance of cortical facilitatory and inhibitory circuits underlies hyperexcitability in ALS.

To determine the relative contribution of inhibitory and facilitatory circuits in the development of cortical hyperexcitability in amyotrophic lateral sclerosis (ALS). In this cross-sectional study, cortical excitability was assessed in 27 patients with ALS, and results compared to 25 healthy controls. In addition, a novel neurophysiologic measure of cortical function, short-interval intracortical facilitation (SICF), was assessed reflecting activity of the facilitatory circuits. There was a significant increase in SICF (ALS -18.51 ± 1.56%, controls -8.52 ± 1.21%, p < 0.001) in patients with ALS that was accompanied by a reduction of short-interval intracortical inhibition (ALS 3.94 ± 1.29%, controls 14.23 ± 1.18%, p < 0.001) and cortical silent period duration (p = 0.034). The index of excitation, a biomarker reflecting the contribution of inhibitory and facilitatory circuit activity, was significantly increased in patients with ALS (82.79 ± 6.01%) compared to controls (36.15 ± 3.44, p < 0.001), suggesting a shift toward cortical excitation. Increased excitation correlated with upper motor neuron signs (R 2 = 0.235, p = 0.016) and greater functional disability as reflected by a correlation with the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised score (R 2 = 0.335, p = 0.002). The present study established that cortical hyperexcitability is a key contributor to ALS pathophysiology, mediated through dysfunction of inhibitory and facilitatory intracortical circuits. Therapies aimed at restoring the cortical inhibitory imbalance provide novel avenues for future therapeutic targets.

Impairments in Motor Neurons, Interneurons and Astrocytes Contribute to Hyperexcitability in ALS: Underlying Mechanisms and Paths to Therapy.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterised by the loss of motor neurons leading to progressive paralysis and death. Using transcranial magnetic stimulation (TMS) and nerve excitability tests, several clinical studies have identified that cortical and peripheral hyperexcitability are among the earliest pathologies observed in ALS patients. The changes in the electrophysiological properties of motor neurons have been identified in both sporadic and familial ALS patients, despite the diverse etiology of the disease. The mechanisms behind the change in neuronal signalling are not well understood, though current findings implicate intrinsic changes in motor neurons and dysfunction of cells critical in regulating motor neuronal excitability, such as astrocytes and interneurons. Alterations in ion channel expression and/or function in motor neurons has been associated with changes in cortical and peripheral nerve excitability. In addition to these intrinsic changes in motor neurons, inhibitory signalling through GABAergic interneurons is also impaired in ALS, likely contributing to increased neuronal excitability. Astrocytes have also recently been implicated in increasing neuronal excitability in ALS by failing to adequately regulate glutamate levels and extracellular K+ concentration at the synaptic cleft. As hyperexcitability is a common and early feature of ALS, it offers a therapeutic and diagnostic target. Thus, understanding the underlying pathways and mechanisms leading to hyperexcitability in ALS offers crucial insight for future development of ALS treatments.

Axonal Excitability in Amyotrophic Lateral Sclerosis : Axonal Excitability in ALS.

Axonal excitability testing provides in vivo assessment of axonal ion channel function and membrane potential. Excitability techniques have provided insights into the pathophysiological mechanisms underlying the development of neurodegeneration and clinical features of amyotrophic lateral sclerosis (ALS) and related neuromuscular disorders. Specifically, abnormalities of Na+ and K+ conductances contribute to development of membrane hyperexcitability in ALS, thereby leading to symptom generation of muscle cramps and fasciculations, in addition to promoting a neurodegenerative cascade via Ca2+-mediated processes. Modulation of axonal ion channel function in ALS has resulted in significant symptomatic improvement that has been accompanied by stabilization of axonal excitability parameters. Separately, axonal ion channel dysfunction evolves with disease progression and correlates with survival, thereby serving as a potential therapeutic biomarker in ALS. The present review provides an overview of axonal excitability techniques and the physiological mechanisms underlying membrane excitability, with a focus on the role of axonal ion channel dysfunction in motor neuron disease and related neuromuscular diseases.

Riluzole exerts transient modulating effects on cortical and axonal hyperexcitability in ALS

Riluzole is an established therapy for amyotrophic lateral sclerosis (ALS), although its effects are modest, prolonging survival by three months on average. While the neuroprotective effects of riluzole appear to be mediated by inhibition of glutaminergic transmission and antagonization of Na+ channel function, the duration of these effects remains to be elucidated. Consequently, the present study combined assessment of cortical and peripheral function to determine the longitudinal effects of riluzole in ALS patients. Assessment of cortical function by threshold tracking transcranial magnetic stimulation (TMS) combined with peripheral nerve function excitability studies were longitudinally undertaken on 19 sporadic ALS patients, with assessment occurring at baseline, four, eight, and 12 weeks post riluzole initiation. Baseline results were compared to 31 healthy controls. Results showed that, at baseline, cortical hyperexcitability was a feature of ALS as indicated by a marked reduction in averaged short interval intracortical inhibition [SICI] (3.6 ± 6.9%, p < 0.0001) and cortical silent period duration (p < 0.05) as well as an increase in motor evoked potential amplitude (p < 0.05). Riluzole therapy resulted in individual patient increase in SICI of 4.3% (p < 0.01) and 5.2% (p < 0.01) at four and eight weeks, respectively. At a peripheral level, riluzole therapy lead to a transient increase at four weeks in the relative refractory period (p < 0.05), superexcitability (p < 0.05) and late subexcitability (p < 0.05), all of which returned to baseline levels eight weeks after initiation of riluzole. In conclusion, the present study has established that riluzole exerts transient effects on cortical and axonal hyperexcitability, potentially accounting for the modest clinical effectiveness in ALS.

7. Pathophysiological basis of motor neuronal hyperexcitability in amyotrophic lateral sclerosis

Objective Motor neuronal hyperexcitability potentially contributes to motor neuron death in amyotrophic lateral sclerosis (ALS). We aimed to reveal pathomechanisms of motor neuron hyperexcitability in ALS. Methods Threshold tracking transcranial magnetic stimulation and multiple excitability measurements were performed in 130 healthy controls (HC), 83 sporadic ALS (sALS) patients, 11 patients with superoxide dismutase-1 (SOD-1) mutations, 16 C9orf72 hexanucleotide repeat expansions and 2 FUS mutations. Results Compared to HC, in peripheral nerve excitability sALS had greater strength-duration time constant (p 0.05), depolarizing threshold electrotonus (p 0.0001) and superexcitability (p 0.05) and smaller late subexcitability (p 0.05). In cortical excitability, sALS had reduced short interval intracortical inhibition (p 0.0001). These indices were not significantly different in SOD-1 and C9orf72, compared to sALS. Conclusion These findings suggest both sALS and familial ALS have increased sodium currents, decreased potassium currents, rendering to peripheral nerve hyperexcitability. In addition, all ALS patients demonstrated decreased intracortical inhibition. Significance Motor neuronal hyperexcitability may be a common feature in both sALS and familial ALS associated with different pathological bases.

19. Cortical hyperexcitability in ALS: A heterogeneous process

Objective Cortical hyperexcitability, as heralded by reduced short interval intracortical inhibition (SICI) has been identified as an intrinsic feature of amyotrophic lateral sclerosis (ALS). However, in approximately 20% of patients cortical excitability may be normal, suggesting the presence of pathophysiological heterogeneity. Consequently, the present study assessed for the presence of clinical, functional and neurophysiological differences in ALS phenotypes, as defined by cortical hyperexcitability. Methods Cortical excitability was assessed in 62 ALS patients. Clinical, functional and neurophysiological parameters were compared between ALS patients with cortical hyperexcitability (SICI 5.5%) versus those with a “normal” level of cortical excitability (SICI > 5.5%). Results In ALS patients with features of cortical hyperexcitability, there appeared to be an absence of SICI in the early phase (interstimulus interval [ISI] 1–3 ms) with a transition to facilitation at later ISIs (3.5–7 ms). In contrast, ALS patients with normal SICI demonstrated similar levels of inhibition across early and late SICI phases. Of further relevance, ALS patients with abnormal SICI exhibited increased mortality in follow-up. Conclusion Dysfunction in cortical inter-neuronal circuits probed by short latency paired-pulse TMS appears to capture some of the pathophysiological heterogeneity in ALS and may have direct implications for survival.

Cortical Hyperexcitability in Amyotrophic Lateral Sclerosis

Amyotrophiclateralsclerosis(ALS) isadevastatingdiseaseofthe motornervoussystem.Whilemost casesare sporadic, approximately5%to10%ofcasesare familial andresult frommutation in1ofmorethan25knownALS genes.Thesegenesspanasurprisingly broad range of molecular functions, including RNA metabolism, oxidative stress, axonal transport, autophagy, excitability, and immunity.Oneof thegreatmysteries in the field is thatmotorneurondiseaseresultsasaconvergentphenotypefrommutations in this diverse group of genes. Understanding this puzzle is likely keytooptimizingbothclinicaltrialsandpatienttreatmentbecause differentdrugsmayultimatelybenecessaryfortargetingspecific disease variants. Despitethemolecularheterogeneity, theclinicalmotorneuronphenotypesresultingfromthevariousgeneticmutationsand sporadic casesdifferonlymodestly. So toohasbeen thecaseon theneurophysiological level, inwhichBaeandcolleagues1have performedanimpressiveassemblyofstudiesshowingaxonaland cortical hyperexcitability in ALS. Lowermotor neuron studies useaspecializednerveconductionstudyprotocolcalled threshold tracking,whichwasdevelopedbyMogyoroset al.2Changes instimulus intensitynecessarytogeneratecompoundmotoractionpotentialsofapredeterminedamplitudearemonitoredduring the course of a recording, andprepulses and recovery cycle analysisareusedtomeasuredifferentcomponentsofaxonalexcitability.Cortical hyperexcitability inALShasbeen repeatedly demonstrated using transcranial magnetic stimulation (TMS), bothusing the traditional constant stimulus technique toelicit motor-evokedpotentials (MEPs)andbyadaptingthethresholdtracking approach to TMS. Inthis issueofJAMANeurology,Geevasingaandcolleagues3 extendedtheirobservationstoshowcorticalhyperexcitability in patients with familial ALS due to chromosome 9 open reading frame72(c9orf72)hexanucleotidegenerepeatexpansion,which is themost commongenetic causeofALSand is responsible for about5%ofapparentsporadicALSand40%offamilialALScases. The findings are quite similar to those in sporadic and superoxidedismutase(SOD1)genefamilialALS,with increasedexcitabilitymanifestedmost clearlyusingpaired testing. Short intracortical inhibitionreferstotheincreaseinMEPthreshold(ordecrease inMEPamplitude) resulting fromaconditioningprepulsea few millisecondsbefore a test pulse. In contrast, intracortical facilitationisthereductioninthreshold(orincreaseinMEPamplitude) whentheconditioningprepulseprecedesthetestpulsebyabout 15milliseconds.4The reduction in short intracortical inhibition and increase in intracortical facilitationare2of themostprominentTMSfindings inALS.Otherdisease featuressharedbyboth sporadicandc9orf72 familialALS includereducedrestingmotor threshold, increased MEP amplitude, decreased cortical silent periodduration, and increased centralmotor conduction time. Thecorticalandaxonalexcitabilitystudieshaveshownaremarkableconsistencyof findings inbothpatientswithsporadic ALSandpatientswithfamilialALSand,thus,raisequestionsabout how different molecular mechanisms converge to produce changes inneuronalexcitability inALSandwhether researchers can leverage the consistent neurophysiological hyperexcitabilityphenotypetoreveal informationandpotential targetsthatare broadlyrelevantacrossALSvariants.Theclinical resultssuggest anopportunitytoreexaminehyperexcitabilityusinganimalmodelsandmore-reductionistsystemstoaddressexcitabilitymechanisms.Suchworkcouldpotentially reveal specific ionchannels or cellular pathways that underlie the neurophysiological phenotype.Thecomplexityofdifferentneuronal andnonneuronal cellularsubtypesthatgiverisetoandmodulatethedifferentTMS and nerve conduction study measurements justify additional basic exploration.However, technical considerationshave limited theuseof theneurophysiological techniques inmice, both with regard to challenges inperforming tests aswell as artifacts owing to sedation in interpreting test results. In animalmodels of SOD1 ALS, most studies have supported increased motor neuronactivity5;however,others, includingastudyusinginvivo recordings of specificmotor neuron pools, have not.6 Inmotor neuronsmadefromALS-inducedpluripotent stemcells,hyperexcitability ispresentbut thendecreaseswith longcultureperiods, potentially because of worsening neuronal health and a depolarization-inducedblockofmotorneuronfiring.7-9 Invitro studies have identified roles of persistent sodium currents and delayed-rectifierpotassiumcurrents in increasingmotorneuron excitability in ALS. Futurework using specific channelmodifiers may help elucidate the channels, receptors, andmolecular scaffolding underlying clinical neurophysiological cortical and axonal hyperexcitability. Webelievethebulkoftheevidencesupportshyperexcitability as aprimaryprocess inALSasopposed toanadaptiveone.10 Thepresenceofsignsofhyperexcitability,suchasfasciculations, beforeotherclinicalsymptomsismoreconsistentwithaprimary roleforhyperexcitability.Similarly,thehyperexcitabilityobserved inbothprenatalSOD1motorneuronsandALSstemcell–derived motorneuronsofmultiplegeneticvariants, inwhichdecreasing excitability improvesmotorneuronsurvival andreducesendoplasmicreticulumstressinvitro,bothsupportaprimaryupstream Author Audio Interview at jamaneurology.com

P850: Electrophysiological pattern in GLUT1 deficiency syndrome (A275T mutation)

s of Poster Presentations / Clinical Neurophysiology 125, Supplement 1 (2014) S1–S339 S269 Figure 2. The relationship between muscle strength and transcranial stimulation motor evoked potential. Conclusions: There is the positive relation between the MEP amplitude and the muscle strength. So, the fixed quantity evaluation method using the statistical technique makes TCS-MEP reliable. And TCS-MEP may enhance us to remove tumors in central nervous system and at the same time preserve motor functions. Moreover this relation between MEP and muscle strength is useful for understanding the motor control system. P850 Electrophysiological pattern in GLUT1 deficiency syndrome (A275T mutation) C. Giliberto1, V. Sofia1, R. Barone2, R. Guerrini3, M. Zappia1 1University of Catania, Department G.F. Ingrassia, Section of Neurosciences, Catania, Italy; 2University of Catania, Pediatric Neurology, Department of Pediatrics, Catania, Italy; 3University of Florence, Pediatric Neurology, Unit and Laboratories, Children’s Hospital A. Meyer, Florence, Italy Question: Glucose transporter type 1 deficiency syndrome (GLUT1DS) is characterized by impaired glucose transport across the blood-brain barrier due to SLC2A1-gene mutation. GLUT1DS infancy onset shows epileptic encephalopathy, ataxia and microcephaly although paroxysmal exerciseinduced dyskinesia and epilepsy may also be observed. Exercise and recovery-induced modifications of GLUT4 and GLUT1 expression in human muscle have been reported.We describe clinical and electromyographyc correlates of a GLUT1DS patient with adult-onset of exercise-induced dystonia. Patients and methods: A 19 year old male with mild mental retardation presented with a two-year history of episodic stiffness in his calves and feet and painless flexion of the toes followed by leg weakness triggered by exertion and starvation and alleviated by rest and eating. His father had experienced exercise-induced leg dystonia at younger age. A heterozygous missense of mutation (c.823G>A; p.A275T) of SLC2A1 gene was found in the proband and his father.The proband underwent an electromyographyc study after voluntary contraction (5 minutes) to investigate muscle membrane excitability with the evaluation of compound muscle action potential (CMAP) amplitude. Results: The test disclosed significant decrement of CMAP amplitude up to −42% (n.v.≤−20%) after 40 minutes from exercise with respect to the pre-exercise CMAP amplitude (baseline). The same test repeated after carbohydrate-rich food intake showed a significant improvement of CMAP from baseline (−26%). Conclusions: The electrophysiological study after exercise showed a reduction of CMAP amplitude in this patient with GLUT1DS (A275T mutation). Our data suggest a possible involvement of muscle membrane excitability in GLUT1DS. P851 Tracking the spatiotemporal profile of cortical and peripheral motor axon hyperexcitability in amyotrophic lateral sclerosis E. Bakola1, P. Kokotis1, R. Carr2, M. Schmelz2, M. Rentzos1, T. Zambelis1, N. Karandreas1 1University of Athens, Medical School, Department of Neurology, Athens, Greece; 2University of Heidelberg, Mannheim Medical School, Department of Anesthesiology, Mannheim, Germany Question: Recent studies using magnetic and electrical excitability tracking tools have confirmed early hyperexcitability in ALS. This study sets out to use excitability testing to examine directly the spatiotemporal profile of cortical and peripheral hyperexcitability in ALS patients simultaneously, to associate these parameters to the clinical course of the disease and to compare them with healthy controls. Methods: Nineteen patients with first-diagnosed definite ALS (group A), four patients with advanced disease (group B) and ten control healthy volunteers (group C) were included in the study. Multiple axonal excitability properties (threshold electrotonus, strength-duration time constant, recovery cycle, current-threshold relationship) and TMS investigations including measurement of resting motor threshold (RMT) and motor evoked potential (MEP) were measured. Results: In group A there were greater changes in depolarizing threshold electrotonus (TD) compared with group B (t-test p<0.03). No differences in recovery cycle, strength-duration time constant, current-threshold relationship were noted between the three groups. Regarding the cortical excitability parameters, there was a significant decrease in the slope of MEP amplitude to TMS intensity in group B with the advanced disease in comparison to controls (Mann-Whitney U test p<0.05). ANCOVA showed strong correlation between TD and slope of cortical excitability (p<0.01) after correcting for the status of the disease (groups A,B,C). Conclusions: These are preliminary results of an ongoing study trying to understand the changes in axonal and cortical excitability in first-diagnosed and advanced disease in order to provide insight into the pathophysiological basis of the disease and furthermore provide useful information for the best treatment approach in the future.

O54: Diagnostic utility of cortical hyperexcitability in amyotrophic lateral sclerosis

O54: Diagnostic utility of cortical hyperexcitability in amyotrophic lateral sclerosis

P851: Tracking the spatiotemporal profile of cortical and peripheral motor axon hyperexcitability in amyotrophic lateral sclerosis

P851: Tracking the spatiotemporal profile of cortical and peripheral motor axon hyperexcitability in amyotrophic lateral sclerosis