[Novel immunomodulatory therapies in myasthenia gravis]. / Myasthénie grave : nouvelles thérapies immunosuppressives.

Myasthenia gravis (MG) is an autoimmune disease characterized by fluctuating weakness of skeletal muscles. Despite current treatments, a significant percentage of patients remain symptomatic. This review explores new immunosuppressive therapies and ongoing clinical trials in MG, including depletion of B lymphocytes with agents such as rituximab and inebilizumab, as well as the use of eculizumab, efgartigimod, satralizumab, tocilizumab, and CAR-T (Chimeric Antigen Receptor-T) cell therapy. These advancements aim to improve disease control and patients' quality of life.

La myasthénie grave (MG) est une maladie auto-immune caractérisée par une faiblesse fluctuante des muscles squelettiques. Malgré les traitements classiques, un pourcentage significatif de patients reste symptomatique. Cet article explore les nouvelles thérapies immunosuppressives et les essais cliniques en cours pour la MG, notamment la déplétion des lymphocytes B avec des agents tels que le rituximab et l'inébilizumab, ainsi que l'utilisation de l'éculizumab, de l'efgartigimod, du satralizumab, du tocilizumab et de la thérapie par cellules CAR-T (Chimeric Antigen Receptor-T). Ces avancées visent à améliorer le contrôle de la maladie et la qualité de vie des patients.

Guillain-Barré syndrome after SARS-CoV-2 infection in an international prospective cohort study.

In the wake of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, an increasing number of patients with neurological disorders, including Guillain-Barré syndrome (GBS), have been reported following this infection. It remains unclear, however, if these cases are coincidental or not, as most publications were case reports or small regional retrospective cohort studies. The International GBS Outcome Study is an ongoing prospective observational cohort study enrolling patients with GBS within 2 weeks from onset of weakness. Data from patients included in this study, between 30 January 2020 and 30 May 2020, were used to investigate clinical and laboratory signs of a preceding or concurrent SARS-CoV-2 infection and to describe the associated clinical phenotype and disease course. Patients were classified according to the SARS-CoV-2 case definitions of the European Centre for Disease Prevention and Control and laboratory recommendations of the World Health Organization. Forty-nine patients with GBS were included, of whom eight (16%) had a confirmed and three (6%) a probable SARS-CoV-2 infection. Nine of these 11 patients had no serological evidence of other recent preceding infections associated with GBS, whereas two had serological evidence of a recent Campylobacter jejuni infection. Patients with a confirmed or probable SARS-CoV-2 infection frequently had a sensorimotor variant 8/11 (73%) and facial palsy 7/11 (64%). The eight patients who underwent electrophysiological examination all had a demyelinating subtype, which was more prevalent than the other patients included in the same time window [14/30 (47%), P = 0.012] as well as historical region and age-matched control subjects included in the International GBS Outcome Study before the pandemic [23/44 (52%), P = 0.016]. The median time from the onset of infection to neurological symptoms was 16 days (interquartile range 12-22). Patients with SARS-CoV-2 infection shared uniform neurological features, similar to those previously described in other post-viral GBS patients. The frequency (22%) of a preceding SARS-CoV-2 infection in our study population was higher than estimates of the contemporaneous background prevalence of SARS-CoV-2, which may be a result of recruitment bias during the pandemic, but could also indicate that GBS may rarely follow a recent SARS-CoV-2 infection. Consistent with previous studies, we found no increase in patient recruitment during the pandemic for our ongoing International GBS Outcome Study compared to previous years, making a strong relationship of GBS with SARS-CoV-2 unlikely. A case-control study is required to determine if there is a causative link or not.

[Small fiber neuropathy in systemic autoimmune diseases]. / Neuropathie des petites fibres dans les maladies autoimmunes systémiques.

Small fiber neuropathy (SFN) causes damage to small-calibre nerve fibers (unmyelinated C fibers and myelinated A-delta fibers). The symptoms of SFN usually are sensitive including paresthesia, dysesthesia or burning pain, and protopathic deficits, sometimes associated with dysautonomia. The causes of SFN can be classified in six main groups: idiopathic, toxic, metabolic, immunological, infectious and hereditary. In this article, we present the diagnostic approach to SFN, the most common autoimmune aetiologies, as well as elements of their therapeutic management.

La neuropathie des petites fibres (NPF) implique une atteinte des fibres nerveuses de petit calibre : les fibres C non myélinisées et les fibres A-delta myélinisées. Elle se manifeste principalement par des troubles sensitifs : paresthésies, dysesthésies ou douleurs neuropathiques (brûlures) et déficits protopathiques, associés à des symptômes dysautonomiques. Les étiologies possibles des NPF sont variées : idiopathiques, toxiques, métaboliques, immunologiques, infectieuses et héréditaires. Nous présentons dans cet article la démarche diagnostique des NPF, les étiologies autoimmunes les plus fréquemment associées aux NPF, ainsi que des éléments de prise en charge thérapeutique.

Clinical evoked potentials in neurology: a review of techniques and indications.

Evoked potentials (EPs) are a powerful and cost-effective tool for evaluating the integrity and function of the central nervous system. Although imaging techniques, such as MRI, have recently become increasingly important in the diagnosis of neurological diseases, over the past 30 years, many neurologists have continued to employ EPs in specific clinical applications. This review presents an overview of the recent evolution of 'classical' clinical applications of EPs in terms of early diagnosis and disease monitoring and is an extension of a previous review published in this journal in 2005 by Walsh and collaborators. We also provide an update on emerging EPs based on gustatory, olfactory and pain stimulation that may be used as clinically relevant markers of neurodegenerative disorders such as Parkinson's disease, Alzheimer's disease and cortical or peripheral impaired pain perception. EPs based on multichannel electroencephalography recordings, known as high-density EPs, help to better differentiate between healthy subjects and patients and, moreover, they provide valuable spatial information regarding the site of the lesion. EPs are reliable disease-progression biomarkers of several neurological diseases, such as multiple sclerosis and other demyelinating disorders. Overall, EPs are excellent neurophysiological tools that will expand standard clinical practice in modern neurology.

Continuous Intraoperative Monitoring of Temporal Lobe Epilepsy Surgery.

BACKGROUND/AIMS: The monitoring of interictal epileptiform discharge rates (IEDRs) all along anterior temporal lobe resections (ATLRs) has never been reported. Here the effect of ATLR on continuous IEDR monitoring is described. METHODS: IEDRs computed automatically during entire interventions were recorded in 34 patients (38.2%, 13/34 depth; 61.8%, 21/34 scalp electrodes only). Monitorings were invalidated when burst suppression occurred or if initial IEDRs were <5. RESULTS: Monitoring was successful for 69.2% (9/13) of the patients with depth recordings and for 4.8% (1/21) of the patients with scalp recordings. Burst suppressions precluded it in 30.8% (4/13) of the depth and in 57.1% (12/21) of the scalp recordings. Initial IEDRs were <5 for 38.1% (8/21) of the scalp recordings. Significant IEDR decreases were observed in 8/10 patients with successful monitoring. These decreases started with resection of the superior temporal gyrus. IEDRs decreased further with amygdalohippocampectomy in 3/5 patients. At the 12-month follow-up, all patients with IEDR decreases remained seizure free; both patients without did not. CONCLUSION: IEDR monitoring was possible with depth, but not with scalp electrodes. IEDR decreases started with resection of the superior temporal gyrus. A larger patient cohort is necessary to confirm the high predictive values of IEDR monitoring that could become a tool for surgery customization.

Paroxysmal painful tonic spasms in neuromyelitis optica spectrum disorder.

Background: Recently, an association between painful tonic spasms (PTS) and Neuromyelitis Optica Spectrum Disorder (NMOSD) was established. Objective: To describe the clinical characteristics of PTS in NMOSD based on a video recording and to provide a literature review on the topic. Methods: We report a case of a 38 years-old woman with a diagnosis of NMOSD and positive aquaporin-4 IgG antibody status who developed PTS five weeks after an episode of longitudinal extensive transverse myelitis (LETM). Results: Repetitive, brief, and painful episodes of muscle contraction were observed on the patient's left hand, spreading to the left arm, and then extending to the four limbs. While pregabalin and topiramate had no influence on these episodes, the patient responded to carbamazepine (CBZ), without symptom recurrence after one year. Conclusions: PTS in association with LETM can be considered typical for NMOSD. Although the exact mechanism is unknown, ephaptic transmission after spinal cord damage and excitatory soluble factors released during acute inflammation responses are sought to be involved. Symptomatic treatment with CBZ achieved remission of spams in our case.

Emerging biomarkers to predict clinical outcomes in Guillain-Barré syndrome.

INTRODUCTION: Guillain-Barré syndrome (GBS) is an immune-mediated poly(radiculo)neuropathy with a variable clinical outcome. Identifying patients who are at risk of suffering from long-term disabilities is a great challenge. Biomarkers are useful to confirm diagnosis, monitor disease progression, and predict outcome. AREAS COVERED: The authors provide an overview of the diagnostic and prognostic biomarkers for GBS, which are useful for establishing early treatment strategies and follow-up care plans. EXPERT OPINION: Detecting patients at risk of developing a severe outcome may improve management of disease progression and limit potential complications. Several clinical factors are associated with poor prognosis: higher age, presence of diarrhea within 4 weeks of symptom onset, rapid and severe weakness progression, dysautonomia, decreased vital capacity and facial, bulbar, and neck weakness. Biological, neurophysiological and imaging measures of unfavorable outcome include multiple anti-ganglioside antibodies elevation, increased serum and CSF neurofilaments light (NfL) and heavy chain, decreased NfL CSF/serum ratio, hypoalbuminemia, nerve conduction study with early signs of demyelination or axonal loss and enlargement of nerve cross-sectional area on ultrasound. Depicting prognostic biomarkers aims at predicting short-term mortality and need for cardio-pulmonary support, long-term patient functional outcome, guiding treatment decisions and monitoring therapeutic responses in future clinical trials.

Specificity of Quantitative Functional Brain Mapping with Arterial Spin-Labeling for Preoperative Assessment.

BACKGROUND AND PURPOSE: Arterial spin-labeling is a noninvasive MR imaging technique allowing direct and quantitative measurement of brain perfusion. Arterial spin-labeling is well-established in clinics for investigating the overall cerebral perfusion, but it is still occasionally employed during tasks. The typical contrast for functional MR imaging is blood oxygen level-dependent (BOLD) imaging, whose specificity could be biased in neurologic patients due to altered neurovascular coupling. This work aimed to validate the use of functional ASL as a noninvasive tool for presurgical functional brain mapping. This is achieved by comparing the spatial accuracy of functional ASL with transcranial magnetic stimulation as the criterion standard. MATERIALS AND METHODS: Twenty-eight healthy participants executed a motor task and received a somatosensory stimulation, while BOLD imaging and arterial spin-labeling were acquired simultaneously. Transcranial magnetic stimulation was subsequently used to define hand somatotopy. RESULTS: Functional ASL was found more adjacent to transcranial magnetic stimulation than BOLD imaging, with a significant shift along the inferior-to-superior direction. With respect to BOLD imaging, functional ASL was localized significantly more laterally, anteriorly, and inferiorly during motor tasks and pneumatic stimulation. CONCLUSIONS: Our results confirm the specificity of functional ASL in targeting the regional neuronal excitability. Functional ASL could be considered as a valid supplementary technique to BOLD imaging for presurgical mapping when spatial accuracy is crucial for delineating eloquent cortex.

The behavioral significance of coherent resting-state oscillations after stroke.

Stroke lesions induce not only loss of local neural function, but disruptions in spatially distributed areas. However, it is unknown whether they affect the synchrony of electrical oscillations in neural networks and if changes in network coherence are associated with neurological deficits. This study assessed these questions in a population of patients with subacute, unilateral, ischemic stroke. Spontaneous cortical oscillations were reconstructed from high-resolution electroencephalograms (EEG) with adaptive spatial filters. Maps of functional connectivity (FC) between brain areas were created and correlated with patient performance in motor and cognitive scores. In comparison to age matched healthy controls, stroke patients showed a selective disruption of FC in the alpha frequency range. The spatial distribution of alpha band FC reflected the pattern of motor and cognitive deficits of the individual patient: network nodes that participate normally in the affected functions showed local decreases in FC with the rest of the brain. Interregional FC in the alpha band, but not in delta, theta, or beta frequencies, was highly correlated with motor and cognitive performance. In contrast, FC between contralesional areas and the rest of the brain was negatively associated with patient performance. Alpha oscillation synchrony at rest is a unique and specific marker of network function and linearly associated with behavioral performance. Maps of alpha synchrony computed from a single resting-state EEG recording provide a robust and convenient window into the functionality and organization of cortical networks with numerous potential applications.

Electroencephalographic source imaging: a prospective study of 152 operated epileptic patients.

Electroencephalography is mandatory to determine the epilepsy syndrome. However, for the precise localization of the irritative zone in patients with focal epilepsy, costly and sometimes cumbersome imaging techniques are used. Recent small studies using electric source imaging suggest that electroencephalography itself could be used to localize the focus. However, a large prospective validation study is missing. This study presents a cohort of 152 operated patients where electric source imaging was applied as part of the pre-surgical work-up allowing a comparison with the results from other methods. Patients (n = 152) with >1 year postoperative follow-up were studied prospectively. The sensitivity and specificity of each imaging method was defined by comparing the localization of the source maximum with the resected zone and surgical outcome. Electric source imaging had a sensitivity of 84% and a specificity of 88% if the electroencephalogram was recorded with a large number of electrodes (128-256 channels) and the individual magnetic resonance image was used as head model. These values compared favourably with those of structural magnetic resonance imaging (76% sensitivity, 53% specificity), positron emission tomography (69% sensitivity, 44% specificity) and ictal/interictal single-photon emission-computed tomography (58% sensitivity, 47% specificity). The sensitivity and specificity of electric source imaging decreased to 57% and 59%, respectively, with low number of electrodes (<32 channels) and a template head model. This study demonstrated the validity and clinical utility of electric source imaging in a large prospective study. Given the low cost and high flexibility of electroencephalographic systems even with high channel counts, we conclude that electric source imaging is a highly valuable tool in pre-surgical epilepsy evaluation.

Update in immunosuppressive therapy of myasthenia gravis.

Myasthenia gravis (MG) is an autoimmune disease of the neuromuscular junction. Immunosuppressive treatments are part of the therapeutic armamentarium in MG. Long-term systemic steroid administration carry considerable risks and adverse events. Consequently, steroid-free immunosuppressive therapy is necessary to reduce the dose or discontinue steroids. First immunosuppressive drug trials in MG were performed in the mid-60s using standard and nonspecific immunosuppression. Since then, only few randomized controlled clinical trials were conducted in MG and assesed drug efficacy in terms of its steroid-sparing capacity and the ability to reduce myasthenic signs and symptoms. Treatment strategy in MG is quite challenging, mainly due to the disease heterogeneity in terms of clinical presentation, immunopathogenesis and drug response. To solve this dilemma, emerging treatment are based on biological drugs and use new targets of the immune pathway.

Interleukin 8, a Biomarker to Differentiate Guillain-Barré Syndrome From CIDP.

OBJECTIVE: To determine whether CSF interleukin 8 (IL-8) concentration can help to distinguish Guillain-Barré syndrome (GBS) from chronic inflammatory demyelinating polyneuropathy (CIDP) at the initial stage of the disease. METHODS: We performed retrospective immunoassay of IL-8 in CSF, collected at the University Hospitals of Geneva between 2010 and 2018, from patients diagnosed with GBS (n = 45) and with CIDP (n = 30) according to the Brighton and European Federation of Neurological Societies/Peripheral Nerve Society criteria by a physician blinded to biological results. RESULTS: CSF IL-8 was higher in GBS (median: 83.9 pg/mL) than in CIDP (41.0 pg/mL) (p < 0.001). Receiver operating characteristic analyses indicated that the optimal IL-8 cutoff was 70 pg/mL. Above this value, patients were more likely to present GBS than CIDP (specificity 96.7%, sensitivity 64.4%, positive predictive value [PPV] 96.7%, and negative predictive value [NPV] 64.4%). Among GBS subcategories, IL-8 was higher in acute inflammatory demyelinating polyneuropathy (AIDP, median: 101.8 pg/mL) than in other GBS variants (median: 53.7 pg/mL). In addition, with CSF IL-8 above 70 pg/mL, patients were more likely to present AIDP than acute-onset CIDP (p < 0.001; specificity 100%, sensitivity 78.8%, PPV 100%, and NPV 46.2%) or other CIDP with nonacute presentation (p < 0.0001; specificity 95.8%, sensitivity 78.8%, PPV 96.3%, and NPV 76.7%). CONCLUSION: CSF IL-8 levels can help to differentiate AIDP variant of GBS from CIDP, including acute-onset CIDP, with high specificity and PPV. This may improve early and appropriate treatment. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that CSF IL-8 levels accurately distinguish patients with GBS from those with CIDP.

Rabies vaccination and multiple sclerosis relapse: A retrospective cohort study.

BACKGROUND: No studies assessing rabies vaccine (RV) tolerability in persons with multiple sclerosis (MS) have been conducted. Given the lack of safety data, RV is recommended essentially only for post-exposure prophylaxis, which is difficult to administer effectively in many rabies-endemic countries. We sought to determine whether RV administration as pre-exposure prophylaxis was associated with MS relapse. METHODS: This retrospective cohort study compared the clinical courses of MS patients in the year before and after rabies vaccination. The year before vaccination was defined as the pre-exposure risk period, the three months thereafter as the exposure-risk period, and the following nine months as the post-risk period. All adult MS patients immunized with RV between 2014 and 2018 and with available medical records in the two-year window were included. The primary outcome was the incidence of symptomatic MS relapse in the exposure-risk period versus the pre-exposure period. RESULTS: Fifty-five patients received at least one dose of RV. Most (38/55, 69%) were female; mean age was 38.5 years (SD ±9.2). While 21 (38%) patients experienced 24 relapses in the year before vaccination, only three (5%) experienced one relapse each in the post-vaccination exposure-risk period; three others (5%) experienced a total of four relapses in the subsequent post-risk period. The annualized relapse rates in the pre-exposure, exposure-risk, and post-risk periods were 0.44, 0.22, and 0.10, respectively (rate ratio for exposure-risk to pre-exposure periods, 0.509 [95% CI 0.098-1.677]). CONCLUSIONS: In this cohort, rabies vaccination was not associated with clinical MS relapse. Larger, prospective studies are needed to confirm these results.

Electrical source imaging for presurgical focus localization in epilepsy patients with normal MRI.

PURPOSE: Patients with magnetic resonance (MR)-negative focal epilepsy (MRN-E) have less favorable surgical outcomes (between 40% and 70%) compared to those in whom an MRI lesion guides the site of surgical intervention (60-90%). Patients with extratemporal MRN-E have the worst outcome (around 50% chance of seizure freedom). We studied whether electroencephalography (EEG) source imaging (ESI) of interictal epileptic activity can contribute to the identification of the epileptic focus in patients with normal MRI. METHODS: We carried out ESI in 10 operated patients with nonlesional MRI and a postsurgical follow-up of at least 1 year. Five of the 10 patients had extratemporal lobe epilepsy. Evaluation comprised surface and intracranial EEG monitoring of ictal and interictal events, structural MRI, [(18)F]fluorodeoxyglucose positron emission tomography (FDG-PET), ictal and interictal perfusion single photon emission computed tomography (SPECT) scans. Eight of the 10 patients also underwent intracranial monitoring. RESULTS: ESI correctly localized the epileptic focus within the resection margins in 8 of 10 patients, 9 of whom experienced favorable postsurgical outcomes. DISCUSSION: The results highlight the diagnostic value of ESI and encourage broadening its application to patients with MRN-E. If the surface EEG contains fairly localized spikes, ESI contributes to the presurgical decision process.

Impaired conduction of Ia sensory fibers in multifocal motor neuropathy: An electrophysiological demonstration.

OBJECTIVES: To report the clinical and electrophysiological findings in two patients with multifocal motor neuropathy (MMN) and bilateral absent patellar and Achilles tendon reflexes despite normal strength of quadriceps and calf muscles. METHODS: The medical history and clinical evaluation were completed by electrophysiological tests: sensory and motor nerve conduction studies, needle electromyography, motor-evoked potentials (MEPs) after transcranial magnetic stimulation, patellar T (tendon) responses, quadriceps and soleus H (Hoffman) reflex recordings. RESULTS: In the two patients, history, clinical evaluation, nerve conduction studies, favorable response to intravenous immunoglobulins, and positive anti-GM1 antibodies fulfilled the diagnosis of MMN. The lower limbs were asymptomatic, except for a unilateral weakness of foot dorsiflexion. The patellar and Achilles tendon reflexes disappeared during the course of the disease. The sensory nerve conduction studies were normal or minimally modified, M-wave and MEP/M amplitude ratio to the quadriceps were normal, patellar T (tendon) responses were virtually absent, and H-reflex to the quadriceps and soleus muscles were absent. CONCLUSIONS: These observations, which show the interruption of the reflex afferent pathway, raise the question of Ia afferent involvement in the lower limbs of these two patients with MMN. Further investigations should determine the frequency and significance of these findings in this disorder.

Risk of MS relapse after yellow fever vaccination: A self-controlled case series.

OBJECTIVE: To determine whether live-attenuated yellow fever vaccine (YFV) was associated with MS relapse, we evaluated the clinical courses of 23 patients in the year before and the year after immunization at the university hospital of Geneva, Switzerland. METHODS: This self-controlled retrospective cohort included adult patients with MS receiving YFV between 2014 and 2018 and defined the year before vaccination, the 3 months thereafter, and the 9 months following as the pre-exposure (PEP), exposure-risk (ERP), and postrisk (PRP) periods, respectively. The primary outcome was the relative incidence of relapse in the ERP vs the PEP. Secondary end points included the presence of new T2-weighted (T2) or T1-weighted gadolinium-positive (T1Gd+) MRI lesions. RESULTS: Of 23 patients with MS receiving YFV (20 relapsing MS and 3 primary progressive MS), 17 (74%) were women; mean age was 34 years (SD ±10); and 10 of 23 (40%) were treated with disease-modifying therapies (DMTs). Although 9 patients experienced 12 relapses in the PEP, only one experienced a relapse in the ERP; 3 other patients experienced one relapse each in the PRP. None of the 8 patients receiving natalizumab at the time of vaccination experienced relapse thereafter. In the PEP, ERP, and PRP, 18, 2, and 9 patients had new brain and/or spinal cord lesions on T2 or T1Gd + MRI, respectively. CONCLUSIONS: In this cohort, YF vaccination was associated with neither an increase in MS relapse nor emergence of brain and/or spinal lesions. Further studies are warranted to confirm these findings. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that for persons with MS, YFV may not increase relapse risk.

IL-8 as a potential biomarker in Guillain-Barre Syndrome.

This pilot study was designed to compare the levels of interleukin-8 (IL-8), a pro-inflammatory chemokine, in the cerebrospinal fluid (CSF) of patients with Guillain-Barre syndrome (GBS), chronic inflammatory demyelinating polyneuropathy (CIDP), non-inflammatory polyneuropathy (PNP), and other non-inflammatory neurological diseases (functional syndrome or migraine). The results show elevated CSF IL-8 levels in GBS compared to the other groups (p < 0.05). IL-8 could be considered a potential biomarker to differentiate GBS from CIDP. This distinction could be relevant in terms of therapeutic decisions and functional prognosis.

A mouse model for studying large-scale neuronal networks using EEG mapping techniques.

Human functional imaging studies are increasingly focusing on the identification of large-scale neuronal networks, their temporal properties, their development, and their plasticity and recovery after brain lesions. A method targeting large-scale networks in rodents would open the possibility to investigate their neuronal and molecular basis in detail. We here present a method to study such networks in mice with minimal invasiveness, based on the simultaneous recording of epicranial EEG from 32 electrodes regularly distributed over the head surface. Spatiotemporal analysis of the electrical potential maps similar to human EEG imaging studies allows quantifying the dynamics of the global neuronal activation with sub-millisecond resolution. We tested the feasibility, stability and reproducibility of the method by recording the electrical activity evoked by mechanical stimulation of the mystacial vibrissae. We found a series of potential maps with different spatial configurations that suggested the activation of a large-scale network with generators in several somatosensory and motor areas of both hemispheres. The spatiotemporal activation pattern was stable both across mice and in the same mouse across time. We also performed 16-channel intracortical recordings of the local field potential across cortical layers in different brain areas and found tight spatiotemporal concordance with the generators estimated from the epicranial maps. Epicranial EEG mapping thus allows assessing sensory processing by large-scale neuronal networks in living mice with minimal invasiveness, complementing existing approaches to study the neurophysiological mechanisms of interaction within the network in detail and to characterize their developmental, experience-dependent and lesion-induced plasticity in normal and transgenic animals.