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We proposed that the brain's electrical activity is composed of a sequence of alternating states with repeating topographic spectral distributions on scalp electroencephalogram (EEG), referred to as oscillatory macrostates. The macrostate showing the largest decrease in the probability of occurrence, measured as a percentage (reactivity), during sensory stimulation was labelled as the default EEG macrostate (DEM). This study aimed to assess the influence of awareness on DEM reactivity (DER). We included 11 middle cerebral artery ischaemic stroke patients with impaired awareness having a median Glasgow Coma Scale (GCS) of 6/15 and a group of 11 matched healthy controls. EEG recordings were carried out during auditory 1 min stimulation epochs repeating either the subject's own name (SON) or the SON in reverse (rSON). The DEM was identified across three SON epochs alternating with three rSON epochs. Compared with the patients, the DEM of controls contained more posterior theta activity reflecting source dipoles that could be mapped in the posterior cingulate cortex. The DER was measured from the 1 min quiet baseline preceding each stimulation epoch. The difference in mean DER between the SON and rSON epochs was measured by the salient EEG reactivity (SER) theoretically ranging from −100% to 100%. The SER was 12.4 ± 2.7% (Mean ± standard error of the mean) in controls and only 1.3 ± 1.9% in the patient group (P < 0.01). The patient SER decreased with the Glasgow Coma Scale. Our data suggest that awareness increases DER to SON as measured by SER., We proposed that the brain's electrical activity is composed of a sequence of alternating states with repeating topographic spectral distributions on scalp electroencephalogram (EEG), referred to as oscillatory macrostates. The macrostate showing the largest decrease in the probability of occurrence, measured as a percentage (reactivity), during sensory stimulation was labelled as the default EEG macrostate (DEM). This study aimed to assess the influence of awareness on DEM reactivity (DER). We included 11 middle cerebral artery ischaemic stroke patients with impaired awareness having a median Glasgow Coma Scale (GCS) of 6/15 and a group of 11 matched healthy controls. EEG recordings were carried out during auditory 1 min stimulation epochs repeating either the subject's own name (SON) or the SON in reverse (rSON). The DEM was identified across three SON epochs alternating with three rSON epochs. Compared with the patients, the DEM of controls contained more posterior theta activity reflecting source dipoles that could be mapped in the posterior cingulate cortex. The DER was measured from the 1 min quiet baseline preceding each stimulation epoch. The difference in mean DER between the SON and rSON epochs was measured by the salient EEG reactivity (SER) theoretically ranging from −100% to 100%. The SER was 12.4 ± 2.7% (Mean ± standard error of the mean) in controls and only 1.3 ± 1.9% in the patient group (P < 0.01). The patient SER decreased with the Glasgow Coma Scale. Our data suggest that awareness increases DER to SON as measured by SER.

Attention is an important aspect of human brain function and often affected in neurological disorders. Objective assessment of attention may assist in patient care, both for diagnostics and prognostication. We present a compact test using a combination of a choice reaction time task, eye-tracking and EEG for assessment of visual attention in the clinic. The system quantifies reaction time, parameters of eye movements (i.e. saccade metrics and fixations) and event related potentials (ERPs) in a single and fast (15 min) experimental design. We present pilot data from controls, patients with mild traumatic brain injury and epilepsy, to illustrate its potential use in assessing attention in neurological patients. Reaction times and eye metrics such as fixation duration, saccade duration and latency show significant differences (p <.05) between neurological patients and controls. Late ERP components (200–800 ms) can be detected in the central line channels for all subjects, but no significant group differences could be found in the peak latencies and mean amplitudes. Our system has potential to assess key features of visual attention in the clinic. Pilot data show significant differences in reaction times and eye metrics between controls and patients, illustrating its promising use for diagnostics and prognostication.

Background and Objective: The course of central and peripheral motor recovery after cervical spinal cord injury (SCI) may be investigated by electrophysiological measures. The goal of this study was to compare the 2 over the first year after injury in relation to motor gains. Methods: Compound motor action potentials (CMAPs), motor-evoked potentials (MEPs), and F-waves were recorded from the abductor digiti minimi and CMAP and F-waves from abductor hallucis muscles in 305 patients at about 15 days, 1 month, 3 months, 6 months, and 12 months following an acute traumatic SCI. Results: The MEP amplitudes and F-wave persistences were lower with more severe sensorimotor impairment. They steadily increased in most subgroups within 6 months after SCI. The amplitude of the CMAPs was low for the first 3 months in the most severely affected participants. This was also found for CMAPs from tibial nerve originating well below the cervical lesion level. Improvement in neurophysiological parameters correlated with improved upper extremity motor scores. Conclusion: The results point to a systematic interrelation of corticospinal transmission, spinal motoneuron excitability, and its axon function, respectively. Electrophysiological correlates of neural excitability show distinct spatial and temporal interrelations within central and peripheral motor pathways following acute cervical SCI. A strong secondary deterioration within the peripheral motor system with incomplete or no recovery depends on anatomical distance caudal to lesion and on lesion severity. Electrophysiological assessments may increase the sensitivity of interventional studies in addition to clinical measures.

Functional jerky movements (or functional myoclonus) are commonly seen in patients with functional movement disorder. Positive features both from history and clinical examination are important for the diagnosis. However, due to their heterogeneous and paroxysmal nature a home-made video-recording of the jerky movements can be essential to make the diagnose by a movement disorder specialist. Supportive clinical clues include abrupt symptom onset often triggered by a physical event, whereas entrainment and distractibility are supportive signs during physical examination. Localization of the jerky movements, especially proximal localization, is supportive, and can also be helpful in distinguishing functional jerks from tics and myoclonus, which are the most important differential diagnostic considerations. Additional neurophysiological tests include polymyography and electroencephalography-electromyography (EEG-EMG) co-registration in order to demonstrate a readiness potential (RP). Management includes disease education and specialized physical therapy.

Functional jerky movements (or functional myoclonus) are commonly seen in patients with functional movement disorder. Positive features both from history and clinical examination are important for the diagnosis. However, due to their heterogeneous and paroxysmal nature a home-made video-recording of the jerky movements can be essential to make the diagnose by a movement disorder specialist. Supportive clinical clues include abrupt symptom onset often triggered by a physical event, whereas entrainment and distractibility are supportive signs during physical examination. Localization of the jerky movements, especially proximal localization, is supportive, and can also be helpful in distinguishing functional jerks from tics and myoclonus, which are the most important differential diagnostic considerations. Additional neurophysiological tests include polymyography and electroencephalography-electromyography (EEG-EMG) co-registration in order to demonstrate a readiness potential (RP). Management includes disease education and specialized physical therapy.

Introduction: Recently began the training of professionals in a new modality of short-cycle Higher Technical Programs, in the specialty of Clinical Neurophysiology. This responds to the need of training health professionals in the study of neurological diseases, whose incidence rates have increased in recent years. Transcranial magnetic stimulation is an important tool in the diagnosis and treatment of these diseases. However, there is a lack of a program for the training of students in the study and application of this technique. Objective: Tto design an own course program on the generalities of transcranial magnetic stimulation, for first-year students of Clinical Neurophysiology. Method: A methodological didactic research was carried out using the empirical and theoretical methods, observation, logical historical, documentary and bibliographic study, dialectic, analysis and synthesis, induction and deduction. Results: A program for the course was proposed, structured in seven topics, with a face-to-face character and a duration of 32 hours. The contents were presented by topics, objectives, essential knowledge to acquire, main skills to master and an evaluation system. Conclusions: The application of this program contributes to the development of skills and the successful performance of professionals in training, in the field of knowledge of the transcranial magnetic stimulation technique for the diagnosis and treatment of neurological diseases., Introdução: Iniciou recentemente a formação de profissionais numa nova modalidade de Cursos Técnicos Superiores de Ciclo Curto, na especialidade de Neurofisiologia Clínica. Isso responde à necessidade de formação de profissionais de saúde no estudo das doenças neurológicas. A estimulação magnética transcraniana é uma ferramenta importante no diagnóstico e tratamento dessas doenças. No entanto, falta um programa de treinamento dos alunos no estudo e aplicação desta técnica. Objetivo: Desenhar um programa próprio sobre as generalidades da estimulação magnética transcraniana, para alunos do primeiro ano de Neurofisiologia Clínica. Método: Realizou-se uma investigação metodológica didática utilizando os métodos empírico e teórico de observação, histórico lógico, estudo documental e bibliográfico, dialética, análise e síntese, indução e dedução. Resultados: Foi proposto um programa de curso próprio, estruturado em sete temas, com caráter presencial e duração de 32 horas. Os conteúdos foram apresentados por tópicos, objetivos, conhecimentos essenciais a adquirir, competências principais a dominar e um sistema de avaliação. Conclusões: A aplicação deste programa contribui para o desenvolvimento de competências e o desempenho bem sucedido de profissionais em formação, no domínio do conhecimento da técnica de estimulação magnética transcraniana para o diagnóstico e tratamento de doenças neurológicas., Introducción: Recientemente se inició la formación de profesionales en una nueva modalidad de Programas Técnico Superior de Ciclo Corto, en la especialidad de Neurofisiología Clínica. Esto responde a la necesidad de la formación de profesionales de la salud en el estudio de las enfermedades neurológicas. La estimulación magnética transcraneal constituye una herramienta importante en el diagnóstico y tratamiento de estas enfermedades. Sin embargo, se carece de un programa para la formación de los estudiantes en el estudio y aplicación de esta técnica. Objetivo: Diseñar un programa de curso propio sobre generalidades de la estimulación magnética transcraneal, para estudiantes de primer año de Neurofisiología Clínica. Métodos: Se realizó una investigación didáctica metodológica utilizando los métodos empíricos y teóricos observación, histórico lógico, estudio documental y bibliográfico, dialéctico, análisis y síntesis, inducción y deducción. Resultados: Se propuso un programa para curso propio que se estructuró en siete temas, con carácter presencial y duración de 32 horas. Se presentaron los contenidos por temas, objetivos, conocimientos esenciales a adquirir, habilidades principales a dominar y sistema de evaluación. Conclusiones: La aplicación de este programa contribuye al desarrollo de habilidades y el desempeño exitoso de los profesionales en formación, en el campo del conocimiento de la técnica de estimulación magnética transcraneal para el diagnóstico y tratamiento de las enfermedades neurológicas.

Background and purpose: Some epilepsy syndromes (sleep-related epilepsies, SREs) have a strong link with sleep. Comorbid sleep disorders are common in patients with SRE and can exert a negative impact on seizure control and quality of life. Our purpose was to define the standard procedures for the diagnostic pathway of patients with possible SRE (scenario 1) and the general management of patients with SRE and comorbidity with sleep disorders (scenario 2). Methods: The project was conducted under the auspices of the European Academy of Neurology, the European Sleep Research Society and the International League Against Epilepsy Europe. The framework entailed the following phases: conception of the clinical scenarios; literature review; statements regarding the standard procedures. For the literature search a stepwise approach starting from systematic reviews to primary studies was applied. Published studies were identified from the National Library of Medicine’s MEDLINE database and Cochrane Library. Results: Scenario 1: Despite a low quality of evidence, recommendations on anamnestic evaluation and tools for capturing the event at home or in the laboratory are provided for specific SREs. Scenario 2: Early diagnosis and treatment of sleep disorders (especially respiratory disorders) in patients with SRE are likely to be beneficial for seizure control. Conclusions: Definitive procedures for evaluating patients with SRE are lacking. Advice is provided that could be of help for standardizing and improving the diagnostic approach of specific SREs. The importance of identifying and treating specific sleep disorders for the management and outcome of patients with SRE is underlined.

Synchronized oscillations within and between brain areas facilitate normal processing, but are often amplified in disease. A prominent example is the abnormally sustained beta-frequency (∼20 Hz) oscillations recorded from the cortex and subthalamic nucleus of Parkinson's disease patients. Computational modeling suggests that the amplitude of such oscillations could be modulated by applying stimulation at a specific phase. Such a strategy would allow selective targeting of the oscillation, with relatively little effect on other activity parameters. Here, activity was recorded from 10 awake, parkinsonian patients (6 male, 4 female human subjects) undergoing functional neurosurgery. We demonstrate that stimulation arriving on a particular patient-specific phase of the beta oscillation over consecutive cycles could suppress the amplitude of this pathophysiological activity by up to 40%, while amplification effects were relatively weak. Suppressive effects were accompanied by a reduction in the rhythmic output of subthalamic nucleus (STN) neurons and synchronization with the mesial cortex. While stimulation could alter the spiking pattern of STN neurons, there was no net effect on firing rate, suggesting that reduced beta synchrony was a result of alterations to the relative timing of spiking activity, rather than an overall change in excitability. Together, these results identify a novel intrinsic property of cortico-basal ganglia synchrony that suggests the phase of ongoing neural oscillations could be a viable and effective control signal for the treatment of Parkinson's disease. This work has potential implications for other brain diseases with exaggerated neuronal synchronization and for probing the function of rhythmic activity in the healthy brain.SIGNIFICANCE STATEMENT In Parkinson's disease (PD), movement impairment is correlated with exaggerated beta frequency oscillations in the cerebral cortex and subthalamic nucleus (STN). Using a novel method of stimulation

Misdiagnosis among tremor syndromes is common, and can impact on both clinical care and research. To date no validated neurophysiological technique is available that has proven to have good classification performance, and the diagnostic gold standard is the clinical evaluation made by a movement disorders expert. We present a robust new neurophysiological measure, the tremor stability index, which can discriminate Parkinson’s disease tremor and essential tremor with high diagnostic accuracy. The tremor stability index is derived from kinematic measurements of tremulous activity. It was assessed in a test cohort comprising 16 rest tremor recordings in tremor-dominant Parkinson’s disease and 20 postural tremor recordings in essential tremor, and validated on a second, independent cohort comprising a further 55 tremulous Parkinson’s disease and essential tremor recordings. Clinical diagnosis was used as gold standard. One hundred seconds of tremor recording were selected for analysis in each patient. The classification accuracy of the new index was assessed by binary logistic regression and by receiver operating characteristic analysis. The diagnostic performance was examined by calculating the sensitivity, specificity, accuracy, likelihood ratio positive, likelihood ratio negative, area under the receiver operating characteristic curve, and by cross-validation. Tremor stability index with a cut-off of 1.05 gave good classification performance for Parkinson’s disease tremor and essential tremor, in both test and validation datasets. Tremor stability index maximum sensitivity, specificity and accuracy were 95%, 95% and 92%, respectively. Receiver operating characteristic analysis showed an area under the curve of 0.916 (95% confidence interval 0.797–1.000) for the test dataset and a value of 0.855 (95% confidence interval 0.754–0.957) for the validation dataset. Classification accuracy proved independent of recording device and posture. The tremor stability index can ai

Multifocal visual evoked potential (mf-VEP) represents a new approach to the classical full field (ff-)VEP with separate responses from up to 60 sectors of the visual field. A thorough literature survey of the use of mf-VEP in optic neuritis (ON) and multiple sclerosis (MS) is presented (38 published studies were retrieved). Mf-VEP provides direct topographical information of specific lesions and facilitates investigations on structural-functional correlations thus providing new methods for exploring the interplay between demyelination, atrophy and remyelination in MS. Good correlation was shown between mf-VEP and OCT, ff-VEP, MRI (MTR, DTI), 30-2 standard automated perimetry and low-contrast-visual acuity. All but one study showed superior sensitivity and specificity compared to ff-VEP, especially with regards to small, peripheral lesions or lesions of the upper visual field. Mf-VEP has shown superior sensitivity and specificity than established methods in diagnosing optic nerve lesions and tracking functional recovery following lesions. Abnormal mf-VEP responses in the fellow, non-ON afflicted eye may predict MS risk in ON patients. No standardization currently exists and no direct comparisons in ON and MS between at least 5 different commercially available mf-VEP systems have so far been published. Despite these limitations, mf-VEP is a promising new tool of diagnostic and prognostic value of mf-VEP in ON and MS.

In recent years, several studies have reported a relatively high frequency of polyneuropathy in patients with Parkinson’s disease (PD), in particular, in patients receiving levodopa-carbidopa intestinal gel (LCIG) infusion. In spite of the several patients investigated with nerve conduction studies, no study has prospectively explored a possible central nervous system involvement of patients receiving LCIG infusion. We prospectively evaluated eight PD patients receiving LCIG infusion, who underwent neurophysiological evaluations with nerve conduction studies, visual, somatosensory and motor evoked potentials before LCIG infusion, and 1 and 6 months after. At 6 months follow-up, we found significant reduction in sural nerve SNAP amplitude, increase of central sensory conduction time N22-P40, and increases of central motor conduction time recorded from I dorsal interosseous and tibialis anterior. In PD patients with LCIG infusion, we found a subclinical neurophysiological impairment of both peripheral and central nervous system.

This thesis investigated the underlying physiology of the human facial nerve in health and disease. This involved the translation and optimisation of techniques for determining axonal excitability measures in the human facial nerve. The techniques have proven to be valuable in determining pathophysiology in neuropathies and it was hypothesised that the information they provide may be helpful in understanding facial nerve disorders. The initial studies developed the technique in healthy controls and established normative data (Chapter 1). The initial study in a disease group (Chapter 2) was targeted at a broad cross-section of facial palsy patients to explore the utility of the technique. Findings consistent with membrane hyperpolarisation were demonstrated. Subsequent studies examined specific disease groups including Bell’s palsy (Chapter 3), facial synkinesis (Chapter 4), and assessment of facial nerve function of the contralateral face to facial palsy (Chapter 5). Changes consistent with reduced inward sodium conductances were noted in Bell’s palsy and these occurred in a pattern that has been noted with tetrodotoxin ingestion. In patients with facial synkinesis, changes in excitability were observed that would be consistent with axonal membrane depolarisation and which may predispose to ectopic motor activity. Altered facial nerve function was also noted in recordings from the contralateral face in patients who had experienced facial palsy and the pattern of change varied according to the severity of facial palsy. These changes provide physiological support for treatment of the contralateral face with chemodenervation in patients with facial palsy.

This thesis intends to describe and explain the course of clinical neurophysiological and neuropsychological parameters in patients with hypertensive disorders in pregnancy. We aimed to improve knowledge on cerebral pathophysiological mechanisms of preeclampsia related to signs and symptoms and to explore whether measuring features of these mechanisms with neurophysiological techniques can help to optimize timing of delivery in order to minimize maternal morbidity and maximize neonatal outcome. We compared EEG findings during pregnancy and postpartum in women with normotensive pregnancies and pregnancies complicated by hypertensive disorders. We concluded that women with severe PE show more EEG abnormalities and have impaired mental wellbeing postpartum. We present a study on visual evoked potentials (VEPs). The objective of this study was to compare neurophysiological changes in women with hypertensive disorders of pregnancy using VEPs. We defined reference values for normotensive pregnant women. We concluded in this study that normotensive pregnant women show neurophysiological adaptation to pregnancy of their visual cortex, which seemed to be absent in women with hypertensive disorders of pregnancy. Using Doppler ultrasound we estimated zero flow pressure (ZFP) and cerebral perfusion pressure (CPP) using simultaneously obtained arterial blood pressure and middle cerebral artery blood flow velocity in women with preeclampsia and healthy pregnant controls. Mean ± SD ZFP was lower in patients than in controls whereas CPP was considerably higher, as was the cerebral flow index. In normotensive pregnant women the patellar reflex was cross-sectionally recorded using surface electromyography at four time points during pregnancy and 6-8 weeks postpartum. Latency and amplitude of the compound muscle action potential during normotensive pregnancies showed no changes compared to the non-pregnant state during reproductive age. Latency of the compound muscle action potential

These guidelines provide an up-date of previous IFCN report on "Non-invasive electrical and magnetic stimulation of the brain, spinal cord and roots: basic principles and procedures for routine clinical application" (Rossini et al., 1994). A new Committee, composed of international experts, some of whom were in the panel of the 1994 "Report", was selected to produce a current state-of-the-art review of non-invasive stimulation both for clinical application and research in neuroscience. Since 1994, the international scientific community has seen a rapid increase in non-invasive brain stimulation in studying cognition, brain-behavior relationship and pathophysiology of various neurologic and psychiatric disorders. New paradigms of stimulation and new techniques have been developed. Furthermore, a large number of studies and clinical trials have demonstrated potential therapeutic applications of non-invasive brain stimulation, especially for TMS. Recent guidelines can be found in the literature covering specific aspects of non-invasive brain stimulation, such as safety (Rossi et al., 2009), methodology (Groppa et al., 2012) and therapeutic applications (Lefaucheur et al., 2014). This up-dated review covers theoretical, physiological and practical aspects of non-invasive stimulation of brain, spinal cord, nerve roots and peripheral nerves in the light of more updated knowledge, and include some recent extensions and developments.

Tremor is a cardinal feature of Parkinson's disease and essential tremor, the two most common movement disorders. Yet, the mechanisms underlying tremor generation remain largely unknown. We hypothesized that driving deep brain stimulation electrodes at a frequency closely matching the patient's own tremor frequency should interact with neural activity responsible for tremor, and that the effect of stimulation on tremor should reveal the role of different deep brain stimulation targets in tremor generation. Moreover, tremor responses to stimulation might reveal pathophysiological differences between parkinsonian and essential tremor circuits. Accordingly, we stimulated 15 patients with Parkinson's disease with either thalamic or subthalamic electrodes (13 male and two female patients, age: 50-77 years) and 10 patients with essential tremor with thalamic electrodes (nine male and one female patients, age: 34-74 years). Stimulation at near-to tremor frequency entrained tremor in all three patient groups (ventrolateral thalamic stimulation in Parkinson's disease, P=0.0078, subthalamic stimulation in Parkinson's disease, P=0.0312; ventrolateral thalamic stimulation in essential tremor, P=0.0137; two-tailed paired Wilcoxon signed-rank tests). However, only ventrolateral thalamic stimulation in essential tremor modulated postural tremor amplitude according to the timing of stimulation pulses with respect to the tremor cycle (e.g. P=0.0002 for tremor amplification, two-tailed Wilcoxon rank sum test). Parkinsonian rest and essential postural tremor severity (i.e. tremor amplitude) differed in their relative tolerance to spontaneous changes in tremor frequency when stimulation was not applied. Specifically, the amplitude of parkinsonian rest tremor remained unchanged despite spontaneous changes in tremor frequency, whereas that of essential postural tremor reduced when tremor frequency departed from median values. Based on these results we conclude that parkinsonian rest trem

Neuromuscular ultrasound (NMUS) continues to demonstrate its utility in the evaluation of diseases involving the peripheral nerve and muscle. Despite its numerous advantages, including low cost, lack of radiation and the ability to provide dynamic imaging, it has received a considerable amount of skepticism due to a perceived lack of reliability.

PurposeTraumatic brain injury (TBI) is an important cause of morbidity and mortality in children, and early posttraumatic seizures (EPTS) are a contributing factor to ongoing acute damage. Continuous video-EEG monitoring (cEEG) was utilized to assess the burden of clinical and electrographic EPTS.MethodsEighty-seven consecutive, unselected (mild - severe), acute TBI patients requiring pediatric intensive care unit (PICU) admission at two academic centers were monitored prospectively with cEEG per established clinical TBI protocols. Clinical and subclinical seizures and status epilepticus (SE, clinical and subclinical) were assessed for their relation to clinical risk factors and short-term outcome measures.Key findingsOf all patients, 42.5% (37/87) had seizures. Younger age (p = 0.002) and injury mechanism (abusive head trauma - AHT, p < 0.001) were significant risk factors. Subclinical seizures occurred in 16.1% (14/87), while 6.9% (6/87) had only subclinical seizures. Risk factors for subclinical seizures included younger age (p < 0.001), AHT (p < 0.001), and intraaxial bleed (p < 0.001). SE occurred in 18.4% (16/87) with risk factors including younger age (p < 0.001), AHT (p < 0.001), and intraaxial bleed (p = 0.002). Subclinical SE was detected in 13.8% (12/87) with significant risk factors including younger age (p < 0.001), AHT (p = 0.001), and intraaxial bleed (p = 0.004). Subclinical seizures were associated with lower discharge King's Outcome Scale for Childhood Head Injury (KOSCHI) score (p = 0.002). SE and subclinical SE were associated with increased hospital length of stay (p = 0.017 and p = 0.041, respectively) and lower hospital discharge KOSCHI (p = 0.007 and p = 0.040, respectively).SignificancecEEG monitoring significantly improves detection of seizures/SE and is the only way to detect subclinical seizures/SE. cEEG may be indicated after pediatric TBI, particularly in younger children, AHT cases, and those with intraaxial blood

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by loss of motor neurons and their supporting cells in the brain, brainstem and spinal cord, resulting in muscle paresis and paralysis including the bulbar (speech, chewing, swallowing) and respiratory muscles. The average age at onset is 55 years, and death due to respiratory failure occurs 2-5 years after symptom onset in ~ 85% of cases. Five to 10% of ALS is familial, and about 20% of familial cases are associated with mutations in the superoxide dismutase 1 (SOD1) gene. To date, 118 SOD1 mutations have been reported worldwide (www alsod.org). All are dominantly inherited, except for the D90A mutation, which is typically recessively inherited. D90A homozygous ALS is associated with long (~14 years) survival, and some atypical symptoms and signs. The reason for this is not known. In contrast, most other SOD1 mutations are associated with average survival, while some are associated with aggressive disease having lower motor neuron predominance and survival less than 12 months. The A4V mutation, which is the most frequently occurring SOD1 mutation in the United States, is an example of the latter. Understanding the pathogenic mechanisms of SOD1 mutants causing widely different disease forms like D90A and A4V is of paramount importance. Overwhelming scientific evidence indicates that mutations in the SOD1 gene are cytotoxic by a “gain of noxious” function, which although not fully understood results in protein aggregation and loss of cell function. This thesis explores different ALS-SOD1 gene mutations in British Columbia (BC), Canada. Two hundred and fifty-three ALS patients were screened for SOD1 mutations, and 12 (4.7%) unrelated patients were found to carry one of 5 different SOD1 mutations: A4V (n=2); G72C (n=1); D76Y (n=1); D90A (n=2); and 113T (n=6). Incomplete penetrance was observed in 3/12 families. Bulbar onset disease was not observed in the SOD1 mutation carriers in this st