Development and application of magnetoencephalographic methods in the investigation of the human visual system

This thesis is an exploration of the organisation and functioning of the human visual system using the non-invasive functional imaging modality magnetoencephalography (MEG). Chapters one and two provide an introduction to the ‘human visual system and magnetoencephalographic methodologies. These chapters subsequently describe the methods by which MEG can be used to measure neuronal activity from the visual cortex. Chapter three describes the development and implementation of novel analytical tools; including beamforming based analyses, spectrographic movies and an optimisation of group imaging methods. Chapter four focuses on the use of established and contemporary analytical tools in the investigation of visual function. This is initiated with an investigation of visually evoked and induced responses; covering visual evoked potentials (VEPs) and event related synchronisation/desynchronisation (ERS/ERD). Chapter five describes the employment of novel methods in the investigation of cortical contrast response and demonstrates distinct contrast response functions in striate and extra-striate regions of visual cortex. Chapter six use synthetic aperture magnetometry (SAM) to investigate the phenomena of visual cortical gamma oscillations in response to various visual stimuli; concluding that pattern is central to its generation and that it increases in amplitude linearly as a function of stimulus contrast, consistent with results from invasive electrode studies in the macaque monkey. Chapter seven describes the use of driven visual stimuli and tuned SAM methods in a pilot study of retinotopic mapping using MEG; finding that activity in the primary visual cortex can be distinguished in four quadrants and two eccentricities of the visual field. Chapter eight is a novel implementation of the SAM beamforming method in the investigation of a subject with migraine visual aura; the method reveals desynchronisation of the alpha and gamma frequency bands in occipital and temporal regions contralateral to observed visual abnormalities. The final chapter is a summary of main conclusions and suggested further work.

Investigating the effects of antiepileptic drugs on the electrophysiology of vision

The principal aim of this work was to examine the effects of antiepileptic drugs (AEDs) on vision. Vigabatrin acts by increasing GABA at brain inhibitory synapses by irreversibly binding to GABA-transaminase. Remacemide is a novel non-competitive NMDA receptor antagonist and fast sodium channel inhibitor that results in the inhibition of the NMDA receptors located in the neuronal membrane calcium channels increasing glutamate in the brain. Vigabatrin has been shown to cause a specific pattern of visual field loss, as one in three adults taking vigabatrin have shown a bilateral concentric constriction. Remacemide has unknown effects on vision. The majority of studies of the effects of AEDs on vision have not included the paediatric population due to difficulties assessing visual field function using standard perimetry testing. Evidently an alternative test is required to establish and monitor visual field problems associated with AEDs both in children and in adults who cannot comply with perimetry. In order to test paediatric patients exposed to vigabatrin, a field-specific visual evoked potential was developed. Other tests performed on patients taking either vigabatrin or remacemide were electroretinograms, electro-oculograms, multifocal VEPs and perimetry. Comparing these tests to perimetry results from vigabatrin patients the field specific VEP was found to have a high sensitivity and specificity, as did the 30Hz flicker amplitude. The modified VEP was also found to provide useful results in vigabatrin patients. Remacemide did not produce a similar visual field loss to vigabatrin although macular vision was affected. The field specific VEP is a useful method for detecting vigabatrin associated visual field loss that is well tolerated by young children. This technique combined with the ERG under light adapted (30Hz flicker) condition is presently the superior method for detecting vigabatrin-attributed peripheral field defects present in children below the developmental age of 9. The effects of AEDs on vision should be monitored carefully and the use of multifocal stimulation allows for specific areas of the retina and visual pathway to be monitored.

Study of the cholinergic factors affecting the flash and pattern reversal visual evoked potentials

The effects of cholinergic agents undergoing clinical trials for the treatment of Alzheimer's disease and the anticholinergic agent scopolamine, were investigated on the components of the flash and pattern reversal visual evoked potentials (VEPs) in young healthy volunteers. The effect of recording the flash and pattern reversal VEPs for 13 hours in 5 healthy male volunteers, revealed no statistically significant change in the latency or amplitude measures. Administration of the muscarinic agonist SDZ 210-086 to 16 healthy male volunteers resulted in the reduction of the flash N2-P2 and pattern reversal N75-P100 peak-to-peak amplitudes. These effects on the flash VEP occurred at both doses (0.5 and 1.0 mg/day), but only at the higher dose on the pattern reversal VEP. Administration of the antimuscarinic agent scopolamine to 11 healthy young male volunteers, resulted in a delay of the flash P2 latency but no effect on the pattern reversal P100 latency. The pattern reversal N75-P100 peak-to-peak amplitude was also increased post dosing. The combination of scopolamine with the acetylcholinesterase inhibitor SDZ ENA 713 resulted in no significant effect on the flash and pattern reversal VEPs, suggesting that the effects of scopolamine may have been partially reversed. Topical application of scopolamine in 6 young healthy volunteers also resulted in no statistically significant effects on the flash and pattern reversal VEPs. The selective effect of scopolamine on the flash P2 latency but not on the pattern reversal P100 latency, provided a model whereby new cholinergic agents developed for the treatment of Alzheimer's disease can be investigated on a physiological basis. In addition, the results of this study led to the hypothesis that the selective flash P2 delay in Alzheimer's disease was probably due to a cholinergic deficit in both the tectal pathway from the retina to the visual cortex and the magnocellular path of the geniculostriate pathway, whereas the lack of an effect on the pattern reversal P100 component was probably due to a sparing of the parvocellular geniculostriate pathway.

The chromatic visual evoked response as an indication of visual development

In an endeavour to provide further insight into the maturation of the cortical visual system in human infants, chromatic transient pattern reversal visual evoked potentials to red/green stimuli, were studied in a group of normal full term infants between the ages of 1 and 14 weeks post term in both cross sectional and longitudinal studies. In order to produce stimuli in which luminance cues had been eliminated with an aim to eliciting a chromatic response, preliminary studies of isoluminance determination in adults and infants were undertaken using behavioural and electrophysiological techniques. The results showed close similarity between the isoluminant ratio for adults and infants and all values were close to photometric isoluminance. Pattern reversal VEPs were recorded to stimuli of a range of red/green luminance ratios and an achromatic checkerboard. No transient VEP could be elicited with an isoluminant chromatic pattern reversal stimulus from any infant less than 7 weeks post term and similarly, all infants more than 7 weeks post term showed clear chromatic VEPs. The chromatic response first appeared at that age as a major positive component (P1) of long latency. This was delayed and reduced in comparison to the achromatic response. As the infant grew older, the latency of the P1 component decreased with the appearance of N1 and N by the 10th week post term. This finding was consistent throughout all infants assessed. In a behavioural study, no infant less than 7 weeks post term demonstrated clear discrimination of the chromatic stimulus, while those infants older than 7 weeks could do so. These findings are reviewed with respect to current neural models of visual development.

Electrophysiological studies of the visual pathways in Alzheimer's and Parkinson's disease

It is known that parallel pathways exist within the visual system. These have been described as magnocellular and parvocellular as a result of the layered organisation of the lateral geniculate nucleus and extend from the retina to the cortex. Dopamine (DA) and acetylcholine (ACH) are neurotransmitters that are present in the visual pathway. DA is present in the retina and is associated with the interplexiform cells and horizontal cells. ACH is also present in the retina and is associated with displaced amacrine cells; it is also present in the superior colliculus. DA is found to be significantly depleted in the brain of Parkinson's disease (PD) patients and ACH in Alzheimer's disease (AD) patients. For this reason these diseases were used to assess the function of DA and ACH in the electrophysiology of the visual pathway. Experiments were conducted on young normals to design stimuli that would preferentially activate the magnocellular or parvocellular pathway. These stimuli were then used to evoke visual evoked potentials (VEP) in patients with PD and AD, in order to assess the function of DA and ACH in the visual pathway. Electroretinograms (ERGs) were also measured in PD patients to assess the role of DA in the retina. In addition, peripheral ACH function was assessed by measuring VEPs, ERGs and contrast sensitivity (CS) in young normals following the topical instillation of hyoscine hydrobromide (an anticholinergic drug). The results indicate that the magnocellular pathway can be divided into two: a cholinergic tectal-association area pathway carrying luminance information, and a non-cholinergic geniculo-cortical pathway carrying spatial information. It was also found that depletion of DA had very little effect on the VEPs or ERGs, confirming a general regulatory function for this neurotransmitter.

The development of the visual system in pre-term infants as assessed by electrophysiological techniques

In an endeavour to provide further insight into the maturation of the human visual system, the contiguous development of the pattern reversal VEP, flash VEP and flash ERG was studied in a group of neurologically normal pre-term infants, born between 28 and 35 weeks gestation. Maturational changes were observed in all the evoked electrophysiological responses recorded, these were mainly characterised by an increase in the complexity of the waveform and a shortening in the latency of the response. Initially the ERG was seen to consist of a broad b-wave only, with the a-wave emerging at an average age of 40 weeks PMA. The a-wave showed only a slight reduction in latency and a modest increase in amplitude as the infant grows older, whereas the changes seen in the ERG b-wave were much more dramatic. Pattern reversal VEPs were successfully recorded for the first time during the pre-term period. Flash VEPs were also recorded for comparison. The neonatal pattern reversal VEP consistently showed a major positive component (P1) of long latency. As the infant grew older, the latency of the P1 component decreased and was found to be negatively correlated with PMA at recording. The appearance of the N1 and N2 components became more frequent as the infant matured. The majority of infants were found to be myopic at birth and refractive error was correlated with PMA, with emmetropisation occurring at about 45 weeks PMA. The pattern reversal VEP in response to 2o checks was apparently unaffected by refractive error.