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.

A comparison between static and kinetic visual attention as a means of detecting age-related deterioration of the visual system and driving performance

A critical review of previous research revealed that visual attention tests, such as the Useful Field of View (UFOV) test, provided the best means of detecting age-related changes to the visual system that could potentially increase crash risk. However, the question was raised as to whether the UFOV, which was regarded as a static visual attention test, could be improved by inclusion of kinetic targets that more closely represent the driving task. A computer program was written to provide more information about the derivation of UFOV test scores. Although this investigation succeeded in providing new information, some of the commercially protected UFOV test procedures still remain unknown. Two kinetic visual attention tests (DRTS1 and 2), developed at Aston University to investigate inclusion of kinetic targets in visual attention tests, were introduced. The UFOV was found to be more repeatable than either of the kinetic visual attention tests and learning effects or age did not influence these findings. Determinants of static and kinetic visual attention were explored. Increasing target eccentricity led to reduced performance on the UFOV and DRTS1 tests. The DRTS2 was not affected by eccentricity but this may have been due to the style of presentation of its targets. This might also have explained why only the DRTS2 showed laterality effects (i.e. better performance to targets presented on the left hand side of the road). Radial location, explored using the UFOV test, showed that subjects responded best to targets positioned to the horizontal meridian. Distraction had opposite effects on static and kinetic visual attention. While UFOV test performance declined with distraction, DRTS1 performance increased. Previous research had shown that this striking difference was to be expected. Whereas the detection of static targets is attenuated in the presence of distracting stimuli, distracting stimuli that move in a structured flow field enhances the detection of moving targets. Subjects reacted more slowly to kinetic compared to static targets, longitudinal motion compared to angular motion and to increased self-motion. However, the effects of longitudinal motion, angular motion, self-motion and even target eccentricity were caused by target edge speed variations arising because of optic flow field effects. The UFOV test was more able to detect age-related changes to the visual system than were either of the kinetic visual attention tests. The driving samples investigated were too limited to draw firm conclusions. Nevertheless, the results presented showed that neither the DRTS2 nor the UFOV tests were powerful tools for the identification of drivers prone to crashes or poor driving performance.

Automated assessment of visual fields and their inter-relation to evoked potentials in visual disorders

The Octopus Automated Perimeter was validated in a comparative study and found to offer many advantages in the assessment of the visual field. The visual evoked potential was investigated in an extensive study using a variety of stimulus parameters to simulate hemianopia and central visual field defects. The scalp topography was recorded topographically and a technique to compute the source derivation of the scalp potential was developed. This enabled clarification of the expected scalp distribution to half field stimulation using different electrode montages. The visual evoked potential following full field stimulation was found to be asymmetrical around the midline with a bias over the left occiput particularly when the foveal polar projections of the occipital cortex were preferentially stimulated. The half field response reflected the distribution asymmetry. Masking of the central 3° resulted in a response which was approximately symmetrical around the midline but there was no evidence of the PNP-complex. A method for visual field quantification was developed based on the neural representation of visual space (Drasdo and Peaston 1982) in an attempt to relate visual field depravation with the resultant visual evoked potentials. There was no form of simple, diffuse summation between the scalp potential and the cortical generators. It was, however, possible to quantify the degree of scalp potential attenuation for M-scaled full field stimuli. The results obtained from patients exhibiting pre-chiasmal lesions suggested that the PNP-complex is not scotomatous in nature but confirmed that it is most likely to be related to specific diseases (Harding and Crews 1982). There was a strong correlation between the percentage information loss of the visual field and the diagnostic value of the visual evoked potential in patients exhibiting chiasmal lesions.

The development of calibration and adaptive filtering procedures for neuromagnetic studies of human visual function

This thesis first considers the calibration and signal processing requirements of a neuromagnetometer for the measurement of human visual function. Gradiometer calibration using straight wire grids is examined and optimal grid configurations determined, given realistic constructional tolerances. Simulations show that for gradiometer balance of 1:104 and wire spacing error of 0.25mm the achievable calibration accuracy of gain is 0.3%, of position is 0.3mm and of orientation is 0.6°. Practical results with a 19-channel 2nd-order gradiometer based system exceed this performance. The real-time application of adaptive reference noise cancellation filtering to running-average evoked response data is examined. In the steady state, the filter can be assumed to be driven by a non-stationary step input arising at epoch boundaries. Based on empirical measures of this driving step an optimal progression for the filter time constant is proposed which improves upon fixed time constant filter performance. The incorporation of the time-derivatives of the reference channels was found to improve the performance of the adaptive filtering algorithm by 15-20% for unaveraged data, falling to 5% with averaging. The thesis concludes with a neuromagnetic investigation of evoked cortical responses to chromatic and luminance grating stimuli. The global magnetic field power of evoked responses to the onset of sinusoidal gratings was shown to have distinct chromatic and luminance sensitive components. Analysis of the results, using a single equivalent current dipole model, shows that these components arise from activity within two distinct cortical locations. Co-registration of the resulting current source localisations with MRI shows a chromatically responsive area lying along the midline within the calcarine fissure, possibly extending onto the lingual and cuneal gyri. It is postulated that this area is the human homologue of the primate cortical area V4.

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 investigation of the primary response of the flash visual evoked response

The topographical distribution of the early components of the flash visual evoked response (VER) were investigated using a twenty channel brain mapping system. Thirty subjects, ranging in age from 21 to 84 years, had flash VERs recorded using the standard 10-20 electrode system to a balanced non-cephalic reference. The subjects were divided into three age groups: a young group, a middle group and an older group. The P2 component (positive component around 100-120 msec) of the flash VER was recorded consistently over the occipital region throughout the age range, as was a frontal negative component (N120) of about the same latency. Only the young age group had this single negative component on the frontage channels, whilst the middle age group showed an additional negative component at around 75 msec (N75). Neither group had a recordable P1 component (positive component around 60-75 msec) over the occipital region. The older age group showed both P1 and P2 components over the occipital region with the distribution of the P1 component being more widespread anteriorly. The frontal channels showed both the negative N75 and the later N120 components. The frontal negative components were shown not to be related to the electroretinogram or the balanced non-cephalic reference, but were affected by the type of stimulation. Responses recorded to both pattern reversal and onset/offset stimulation did not show the frontal negative potentials seen with flash stimulation. It was shown that the P1 component is more readily recordable in the elderly and is preceded during middle age by the development of a frontal negative component at around the same latency. The changing morphology of the negative activity in the frontal region across the age range suggests that the use of an Fz reference would produce an artificial P1 component in the middle age group and an enhancement of this component in the elderly, as well as enhance the P2 component in all ages.

Factors affecting the accommodative response to sustained visual tasks

In the absence of adequate visual stimulation accommodation adopts an intermediate resting position, appropriately termed tonic accommodation (TA). A period of sustained fixation can modify the tonic resting position, and indicate the adaptation properties of TA. This thesis investigates various factors contributing to the accommodative response during sustained visual tasks, in particular the adaptation of TA. Objective infra-red optometry was chosen as the most effective method of measurement of accommodation. This technique was compared with other methods of measuring TA and the results found to be well correlated. The inhibitory sympathetic input to the ciliary muscle provides the facility to attenuate the magnitude and duration of adaptive changes in TA. This facility is, however, restricted to those individuals having relatively high levels of pre-task TA. Furthermore, the facility is augmented by substantial levels of concurrent parasympathetic activity. The imposition of mental effort can induce concurrent changes in TA which are predominantly positive and largely the result of an increase in parasympathetic innervation of the ciliary muscle although there is some evidence for sympathetic attentuation at higher levels of TA. In emmetropes sympathetic inhibition can modify the effect of mental effort on the steady-state accommodative response at near. Late-onset myopes (onset after the age of 15 years) have significantlylower values of TA then emmetropes. Similarly, late-onset myopes show lower values of steady-state accommodative response for nearstimuli. The imposition of mental effort induces concurrent increases in TA and steady-state accommodative response in the myopic group which are significantly greater than those for emmetropes. Estimates of TA made under bright empty-field conditions are well correlated with those made under darkroom conditions. The method by which the accommodative loop is opened has no significant effect on the magnitude and duration of post-task shifts in TA induced by a near vision task. Significant differences in the post-task shifts in TA induced by a near vision task exist between emmetropes and late-onset myopes, the post-task shifts being more sustained for the myopic group.

The effect of stimulus location on the major components of the visual evoked response

The topographical distribution of the pattern reversal Visual Evoked Response (VER) was recorded from a localised montage of 20 electrodes over the visual cortex. The response was recorded after stimulation with a black and white checkerboard stimulus. The effect of field location on the major components was investigated in 11 subjects (age range (23-55). The major components of the half field response were; a negative around 75ms (N75) followed by a positivity around 80ms (P80), then a positivity around 100ms (P100) followed by another positivity at around 120ms (P120) and a negativity at approximately 145ms (N145). No effect of field size could be demonstrated on either the amplitude or latency of the late negativity, N145. No significant effect of field size or location was shown on the latency of the P100 response. A delay previously shown in the upper half field response was therefore not substantiated. In contrast the amplitude of the major positivity, P100 was significantly affected by the field size and location. The amplitude of both P100 and N145 were significantly reduced following upper field stimulation when compared with the lower field response. No significant amplitude difference between the upper and lower field responses was demonstrated using electroretinography, the amplitude may therefore be reduced as a result of the ventral position of the upper field representation on the visual cortex. The lateral half field VEP was compared with the distribution of the visual evoked magnetic response (VEMR). The distribution of the VEMR supported the proposal that the paradoxical lateralisation of the VEP half field response is the result of the source being directed ipsilaterally. The morphology of the VEP following octant and double octant stimulation suggests that the response is generated in the striate cortex, with a reversal in response distribution following stimulation of the upper vertical and horizontal meridia.

Investigations into visual hyperacuity

Visual hyperacuities.are a group of thresholds whose values surpass that expected by the anatomical and optical constraints of the eye. There are many variables which affect hyperacuities of which this thesis considers the following .. 1. The effect of contrast on displacement detection and bisection acuity. It is proposed that spatial summation may account for the different response of these two hyperacuities compared with the contrast response of vernier acuity. 2. The effect of references on displacement detection. These were shown to greatly enhance performance when present. Their effect was, however, dependent upon the temporal characteristics of the displacement. 3. The effect of spatial frequency on vernier acuity. Evidence from this experiment suggests that vernier performance can be explained on the basis of the output of orientationally selective spatial frequency filters. 4. Evidence for a weighting function for visual location using random dot clusters. The weighting attached to different parts of the retinal light distribution was found to alter non-linearly with increasing offset from the geometric center of the cluster. A relationship between dot density and peak amplitude of the weighting function was found. 5. Spatial scaling of vernier acuity in the peripheral field. With careful choice of a technique which did not allow separation and eccentricity to co-vary it was found possible to scale vernier acuity both for two lines and two separated dots. 6. The effect of increasing age on hyperacuity. No change in vernier acuity with age was found which contrasted with displacement detection and bisection acuity both of which showed a significant decline with increasing age.

Visual evoked magnetic responses (VEMR) to flash and pattern reversal stimulation

The problems of using a single channel magnetometer (BTi, Model 601) in an unshielded clinical environment to measure visual evoked magnetic responses (VEMR) were studied. VEMR to flash and pattern reversal stimuli were measured in 100 normal subjects. Two components, the P100M to pattern reversal and P2M to flash, were measured successfully in the majority of patients. The mean latencies of these components in different decades of life were more variable than the visual evoked potentials (VEP) that have been recorded to these stimuli. The latency of the P100M appeared to increase significantly after about 55 years of age whereas little change occurred for the flash P2M. The effects of blur, check size, stimulus size and luminance intensity on the latency and amplitude of the VEMR were studied. Blurring a small (32') check significantly increased latency whereas blurring a large (70') check had little effect on latency. Increasing check size significantly reduced latency of the P100M but had little effect on amplitude. Increasing the field size decreases the latency and increases the amplitude of the P100M. Within a normal subject, most of the temporal variability of the P100M appeared to be associated with run to run variation rather than between recording sessions on the same day or between days. Reproducibility of the P100M was improved to a degree by employing a magnetically shielded room. Increasing flash intensity decreases the latency and increases the amplitude of the P2M component. The magnitude of the effects of varying stimulus parameters on the VEMR were frequently greater than is normally seen in the VEP. The topography of the P100M and P2M varied over the scalp in normal subjects. Full field responses to a large check could be explained as approximately the sum of the half field responses and were consistent with the cruciform model of the visual cortex. Preliminary source localisation data suggested a shallower source in the visual cortex for the flash P2M compared with the P100M. The data suggest that suitable protocols could be devised to obtain normative data of sufficient quality to use the VEMR to flash and pattern clinically.

Investigation into visual defects attributed to Vigabatrin

Vigabatrin (VGB) is a transaminase inhibitor that elicits its anitepileptic effect by increasing GABA concentrations in the brain and retina. - Assess whether certain factors predispose patients to develop severe visual field loss. - Develop a sensitive algorithm for investigating the progression of visual field loss. - Determine the most sensitive clinical regimen for diagnosing VGB-attributed visual field loss. - Investigate whether the reports of central retinal sparing are accurate. The investigations have resulted in a number of significant findings: - The anatomical evidence in combination with the pattern of visual field loss suggests that the damage induced by VGB therapy occurs at retinal level, and is most likely a toxic effect. - The quantitative algorithm, designed within the course of this investigation, provided increased sensitivity in determining the severity of visual field loss. - Maximum VGB dose predisposes patients to develop severe visual field loss. - The SITA Standard algorithm was found to be as sensitive and significantly faster, in diagnosing visual field defects attributed to VGB, when compared to the Full Threshold algorithm. The Full Threshold was found to be the most repeatable between visits. - The normal SWAP 10-2 database provided an effective method of differentiating SWAP defects. - SWAP, FDT and the mfERG have increased sensitivity in detecting visual field loss attributed to VGB. The pattern of visual field loss from these investigations suggests that VGB produces a diffuse effect across the retina including subtle central abnormalities and more severe peripheral defects. - Abnormalities detected using the mfERG have suggested that VGB adversely affects the photoreceptors Müller, amacrine and ganglion cells in the retina. An urgent review of the manufacturers recommended maximum dose for VGB is required.

Visual symptoms in Parkinson's disease

Parkinson’s disease (PD) is a common disorder of middle-aged and elderly people in which degeneration of the extrapyramidal motor system causes significant movement problems. In some patients, however, there are additional disturbances in sensory systems including loss of the sense of smell and auditory and/or visual problems. This article is a general overview of the visual problems likely to be encountered in PD. Changes in vision in PD may result from alterations in visual acuity, contrast sensitivity, colour discrimination, pupil reactivity, eye movements, motion perception, visual field sensitivity and visual processing speeds. Slower visual processing speeds can also lead to a decline in visual perception especially for rapidly changing visual stimuli. In addition, there may be disturbances of visuo-spatial orientation, facial recognition problems, and chronic visual hallucinations. Some of the treatments used in PD may also have adverse ocular reactions. The pattern electroretinogram (PERG) is useful in evaluating retinal dopamine mechanisms and in monitoring dopamine therapies in PD. If visual problems are present, they can have an important effect on the quality of life of the patient, which can be improved by accurate diagnosis and where possible, correction of such defects.

Methodology of photic stimulation revisited:updated European algorithm for visual stimulation in the EEG laboratory

Intermittent photic stimulation (IPS) is a common procedure performed in the electroencephalography (EEG) laboratory in children and adults to detect abnormal epileptogenic sensitivity to flickering light (i.e., photosensitivity). In practice, substantial variability in outcome is anecdotally found due to the many different methods used per laboratory and country. We believe that standardization of procedure, based on scientific and clinical data, should permit reproducible identification and quantification of photosensitivity. We hope that the use of our new algorithm will help in standardizing the IPS procedure, which in turn may more clearly identify and assist monitoring of patients with epilepsy and photosensitivity. Our algorithm goes far beyond that published in 1999 (Epilepsia, 1999a, 40, 75; Neurophysiol Clin, 1999b, 29, 318): it has substantially increased content, detailing technical and logistical aspects of IPS testing and the rationale for many of the steps in the IPS procedure. Furthermore, our latest algorithm incorporates the consensus of repeated scientific meetings of European experts in this field over a period of 6 years with feedback from general neurologists and epileptologists to improve its validity and utility. Accordingly, our European group has provided herein updated algorithms for two different levels of methodology: (1) requirements for defining photosensitivity in patients and in family members of known photosensitive patients and (2) requirements for tailored studies in patients with a clear history of visually induced seizures or complaints, and in those already known to be photosensitive.

Abnormal visual habituation in pediatric photosensitive epilepsy

Objective - To investigate visual habituation – a measure of visual cortical excitability – in photosensitive patients in pediatric age and compare the findings with a matched sample with idiopathic generalized epilepsies without photosensitivity and with normally developing children. Methods - We presented a full-field black-and-white checkerboard pattern, at 3 reversal/s with 100% contrast binocularly for 600 consecutive trials and measured the N75–P100 and P100–N145 pattern-reversal visual evoked potential inter-peak amplitudes and N75, P100, N145 latencies for the six blocks of 100 responses. As a measure of habituation we used the slope of the linear regression line of the N75–P100 and P100–N145 peak-to-peak amplitudes. The slope of the linear regression line of the N75–P100 and P100–N145 latencies was also analyzed. Results - Statistical analysis revealed significant differences between the three groups in the slope index of N75–P100 PR-VEP amplitude, with increased or constant amplitude in the PS group compare to the IGE and ND across the six blocks. Conclusions - Our results support the notion that photosensitivity is associated with altered control of excitatory and inhibitory cortical processes. The causal relationship between habituation deficit and photo-paroxysmal response needs to be further investigated with longitudinal studies. Significance This study supports the hypothesis that suppression of PR-VEP is a sensitive intermediate phenotype, which discriminates patients with photosensitivity from those with generalized epilepsies in pediatric age.

Adults with dyslexia demonstrate large effects of crowding and detrimental effects of distractors in a visual tilt discrimination task

Previous research has shown that adults with dyslexia (AwD) are disproportionately impacted by close spacing of stimuli and increased numbers of distractors in a visual search task compared to controls [1]. Using an orientation discrimination task, the present study extended these findings to show that even in conditions where target search was not required: (i) AwD had detrimental effects of both crowding and increased numbers of distractors; (ii) AwD had more pronounced difficulty with distractor exclusion in the left visual field and (iii) measures of crowding and distractor exclusion correlated significantly with literacy measures. Furthermore, such difficulties were not accounted for by the presence of covarying symptoms of ADHD in the participant groups. These findings provide further evidence to suggest that the ability to exclude distracting stimuli likely contributes to the reported visual attention difficulties in AwD and to the aetiology of literacy difficulties. The pattern of results is consistent with weaker and asymmetric attention in AwD.