Aerospace medicine and biology: A continuing bibliography with indexes, supplement 125

This special bibliography lists 323 reports, articles, and other documents introduced into the NASA scientific and technical information system in January 1974

Miller Fisher Syndrome: The Localisation of Pathology

The syndrome described by Miller Fisher (1956) comprises an acute ophthalmoplegia (or ophthalmoparesis) associated with severe ataxia, predominantly of gait and trunk, and a mild to moderate increase in the cerebrospinal fluid protein level unassociated with pleocytosis. As in the Guillain-Barre syndrome, there is usually an antecedent infection commonly of the upper respiratory tract. The illness has a benign course with rapid and usually complete recovery. The precise nature, aetiology and main site of pathological changes in the Miller Fisher syndrome are not well understood and have been the subject of some controversy. Since neuropathological evidence from typical cases of the syndrome is lacking, due to the benign nature of the illness, hypotheses have been based on clinical observations. Opinions have suggested either that the syndrome is related to acute inflammatory demyelinating polyradiculoneuropathy, or, that it is due to a brainstem inflammatory lesion, or, that both such types of component are present. This thesis is an attempt to address the question of identification of the main site of action of the pathological process in the Miller Fisher syndrome. Comprehensive multimodal and serial neurophysiological investigations, testing both the peripheral and central nervous system, have been applied to a group of seven typical patients with the syndrome at standardised intervals from onset of the illness up to and after full recovery. The results are compared with those from 20 patients with classical Guillain-Barre syndrome systematically investigated in a similar way, and with those previously reported in the literature. The findings are then discussed in the context of peripheral versus central nervous system dysfunction. In the first chapter, a review is presented of a small number of reports of similar cases described incompletely prior to Fisher's original 1956 account, followed by an analysis of 84 patients with the syndrome reported in the literature and by an outline of some of the controversies concerning the underlying pathology. Chapter 2 describes the clinical findings together with the course, laboratory investigations and case analysis of 7 patients with typical Miller Fisher syndrome. In chapter 3, the neurophysiological methods and the timing of their application are detailed, together with a critical appraisal of their reliability. The investigations used included: 1. electromyography. 2. nerve conduction studies. 3. late response (H-reflex and F-wave) studies. 4. estimation of motor unit numbers and motor unit potentials analysis. 5. peripheral facial nerve and blink reflex studies. 6. computerised quantitative sensory (thermal and vibration) threshold measurements. 7. muscle silent period studies. 8. multimodal evoked potentials (somatosensory, brainstem auditory and visual) studies. 9. electroencephalography. 10. Quantitative pupillometric and pharmacological observations on the pupils. The results of the neurophysiological investigations and their evolution with time are presented in chapter 4. The findings indicated the presence of a significant dysfunction in the peripheral nerves of the limbs, the facial nerves and in the postganglionic parasympathetic fibres subserving the pupils. They also provided support for a peripheral disturbance as the underlying mechanism for the ataxia observed in patients with the Miller Fisher syndrome. The results of comparably timed, similar comprehensive neurophysiological investigation in 20 patients with the Guillain-Barre syndrome for a total period of 18 months are described in chapter 5. The results are compared with those of other studies from the literature. In chapter 6, the lack of any significant neurophysiological or brain imaging evidence for central nervous system involvement in the group of patients with the Miller Fisher syndrome is outlined. In the main discussion in chapter 7, the neurophysiological findings in the patients with the Miller Fisher syndrome are critically assessed and compared with those from the patients with the Guillain-Barre syndrome in the present study and in reports from the literature. This discussion is set in the context of concepts of peripheral and of central nervous system involvement. Clinical similarities between the Miller Fisher and the Guillain-Barre syndromes are outlined and 20 patients who appear to have overlapping features which suggest a link or continuum between the two syndromes, are reviewed from the literature. (Abstract shortened by ProQuest.)

Multifocal visual evoked potentials in demyelinating diseases of the visual pathway

Multifocal visual evoked potentials (mfVEP) provide an objective functional measure of the integrity of the visual pathway. This thesis constitutes a comprehensive assessment of mfVEP changes in demyelinating diseases of the visual pathway. The efficacy of the mfVEP technique was compared to full-field pattern-reversal visual evoked potential and the results illustrate a superiority of the mfVEP in detecting focal visual field defects in patients with different visual pathway disorders. The evolution of mfVEP parameters’ changes following acute optic neuritis (ON) was assessed in a longitudinal study of affected and fellow eyes in a large cohort of patients during the first 12 months after attack. The results indicated that mfVEP amplitude can be used as an early predictor of post-ON axonal loss. Additionally, the apparently more severe involvement of ON eyes in the MS subgroup may be due to subclinical inflammation along the visual pathway. The analysis of latency delay in fellow eyes in ON patients indicated that the observed changes are most likely due to subclinical demyelination in the visual pathway and a reflection of the burden of disease in MS patients rather than a result of adaptive cortical plasticity to compensate for delayed transmission of visual information. The last study evaluated the relationship between mfVEP latency and posterior visual pathway lesions in MS patients which demonstrated a significant evidence linking the mfVEP changes with retro-geniculate inflammatory demyelinating lesions

Non-invasive electrical and magnetic stimulation of the brain, spinal cord, roots and peripheral nerves: Basic principles and procedures for routine clinical and research application. An updated report from an I.F.C.N. Committee

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

Promoting and measuring remyelination and neuroprotection in clinical trials of people with multiple sclerosis

The most tractable strategy to delay or prevent the progressive phase of MS is to promote endogenous remyelination; doing so restores nerve conduction and prevents demyelinated axons from degenerating. The rate-limiting stage in this process is differentiation of oligodendrocyte progenitor cells (OPCs) into mature, myelinating, oligodendrocytes. In animals, agonism of the retinoid X receptor (RXR)-γ enhances remyelination in this way. Metformin also promotes remyelination, this time by overcoming an age-associated block to the responsiveness of OPCs to pro-differentiation factors. In this PhD I show that bexarotene, a non-selective agonist of the RXR receptor, promotes remyelination in people with relapsing remitting multiple sclerosis. Converging evidence from electrophysiology and neuroimaging in a phase II clinical trial (CCMR One) demonstrate that this occurs in demyelinated lesions and is greatest in lesions located in grey matter regions of the brain. I additionally conducted analyses which suggest an age-dependency of bexarotene’s remyelinating effect and led a follow-up sub study of the trial participants which showed the treatment effect afforded by bexarotene is sustained, years after treatment. Unfortunately, bexarotene was poorly tolerated, and so the legacy of this trial will likely be one of shaping the framework for future assessments of remyelinating therapies. As such, I designed, obtained funding and secured approvals for a clinical trial to test the remyelinating effect of the combination of metformin with clemastine (CCMR Two), implementing lessons from CCMR One in the trial design; this is due to commence participant recruitment in 2021. In exploring treatments for progressive forms of MS, not limited to the process of remyelination, I worked with the MS Society to develop and implement a rigorous, expert-led, evidence-based approach to the selection of licensed drugs for repurposing and testing in clinical trials of people with progressive MS. I reviewed the preclinical and clinical literature for a list of compounds and condensed these into a database of summary documents. These were presented to a panel of experts and people affected by MS, ultimately leading to four treatments being recommended for immediate testing in progressive MS trials: R-α-lipoic acid, metformin, the combination treatment of R-α-lipoic acid and metformin, and niacin. Regrettably, much of my research has been halted by the COVID-19 pandemic. In this PhD I had additionally sought to evaluate electrophysiological techniques for quantifying remyelination and neuroprotection – multifocal VEP and saccadometry – in cohorts of people with MS and in the setting of the CCMR Two trial. Instead, when these studies were delayed, I embraced an opportunity to help the Cambridge COVID-19 research effort, working on the RECOVERY trial in the first wave, and leading my own project to analyse enrolment to treatment trials, ultimately describing the barriers to, and implications of, low recruitment rates in advance of the subsequent waves. Consequently, further exploratory research with electrophysiology and the CCMR Two trial will be the subject of post-doctoral research.Multiple Sclerosis Society of the United Kingdo

Correlated Activity and Corticothalamic Cell Function in the Early Mouse Visual System

Vision has long been the model for understanding cortical function. Great progress has been made in understanding the transformations that occur within some primary visual cortex (V1) layers, like the emergence of orientation selectivity in layer 4. Less is known about other V1 circuit elements, like the shaping of V1 input via corticothalamic projections, or the population structure of the cortico-cortical output in layer 2/3. Here, we use the mouse early visual system to investigate the structure and function of circuit elements in V1. We use two approaches: comparative physiology and optogenetics. We measured the structure of pairwise correlations in the output layer 2/3 using extracellular recordings. We find that despite a lack of organization in mouse V1 seen in other species, the specificity of connections preserves a correlation structure on multiple timescales. To investigate the role of corticogeniculate projections, we utilize a transgenic mouse line to specifically and reversibly manipulate these projections with millisecond precision. We find that activity of these cells results a mix of inhibition and excitation in the thalamus, is not spatiotemporally specific, and can affect correlated activity. Finally, we classify mouse thalamic cells according to stimuli used for cell classification in primates and cats, finding some, but not complete, homology to the processing streams of primate thalamus and further highlighting fundamentals of mammalian visual system organization

Electrophysiological markers for neuropathic pain in spinal cord injured subjects

Physical disability following spinal cord injury (SCI) is the most striking problem noted by the general public. But for the affected subjects urogenital difficulties or depression and pain are often more burdensome. Pain after SCI can have various reasons but only neuropathic pain below the level of lesion (bNP) is thought to be caused by injury of the spinal nervous tissue. This type of pain is in the focus of this thesis. Once bNP has established it is mostly chronic and medication is generally ineffective. Currently, more and more treatments trying to restore function after SCI enter the clinical trial phase. Besides improving function, however, treatments increasing nerve growth in the spinal cord risk to induce or exacerbate bNP. Therefore, observation of bNP is a crucial factor in such interventional studies. A method to objectively supervise bNP has, however, not yet been established. The spinothalamic tract (STT) mainly transmits nociceptive and temperature information in the spinal cord. This tract was dysfunctional in SCI subjects suffering from bNP in clinical examinations. Nevertheless, STT dysfunction was not predictive for bNP and sensory differences between subjects with and without bNP could not be detected. In contrast to clinical examination which is always subjective and only offers limited resolution, electrophysiological measures allow for a more detailed and objective investigation. The novel electrophysiological method of contact heat evoked potentials (CHEP) measures STT function. Establishment of this method was the goal of the first study. The painful stimulation on locations along the spine allowed the calculation of the conduction velocity of the STT in healthy subjects. Furthermore the CHEP latency depended linearly on the heat pain threshold with 1° C higher threshold leading to approximately 10 ms longer latency. It was hypothesized that the rather low heating rate combined with the time-consuming passive heat spread from skin surface to nociceptors was responsible for this. The second study aimed at clarifying this dependence through comparison of the results of study 1 with those of a theoretical heat transfer model. According to this model, 1° C higher pain threshold leads to approximately 15 ms longer CHEP latency. The close similarity between the experimentally determined (study 1) and the computed dependence, proved the influence of the pain threshold on CHEP latency. Summary Electrophysiological markers for Neuropathic Pain in SCI Subjects 2 Subjects suffering from neuropathic pain (NP) in general and not only in SCI, have lowered EEG peak frequency. It was hypothesized in literature that the reduced EEG peak frequency emerged from thalamic deafferentiation and from the ensuing dysrhythmia in thalamocortical feedback loops. Therefore, the third study investigated EEG peak frequency in addition to STT function and compared both between SCI subjects with and without bNP and controls. The STT function (measured with CHEP) below the level of injury was distinctly impaired in SCI compared to control subjects. Furthermore, the EEG peak frequency was generally lower in the SCI subjects. While the CHEP measurements did not reveal differences between subjects with and without bNP, the EEG peak frequency was lowered in subjects with bNP. This difference, however, was only apparent after the linear dependence of EEG peak frequency from the level of SCI was taken into account. In consideration of this dependence, the EEG peak frequency could in future be helpful to supervise bNP both in studies aiming at restoring function or reducing pain after SCI. Currently, the clinical read-out parameter for STT function is pinprick sensation. In the fourth study this pinprick sensation was traced over the first year after SCI. Comparison of this STT function with the bNP state of the same subjects 2-5 years after SCI disclosed larger functional STT recovery in subjects suffering from bNP. Despite the different STT functional recovery, the initial and end measurements did not discriminate between subjects with and without bNP. This was in agreement with earlier studies. The results corroborate the above mentioned hypothesis that new therapies intending to promote sensorimotor recovery after SCI could simultaneously induce bNP by boosting recovery of spinothalamic function