The investigation of oscillatory changes in the visual cortex using synthetic aperture magnetometry

This thesis is an exploration of the oscillatory changes occurring in the visual cortex as measured by a functional imaging technique known as Synthetic Aperture Magnetometry (SAM), and how these compare to the BOLD response, across a number of different experimental paradigms. In chapter one the anatomy and physiology of the visual pathways and cortex are outlined, introducing the reader to structures and terms used throughout the thesis whilst chapter two introduces both the technology and analysis techniques required to record MEG and fMRI and also outlines the theory behind SAM. In chapter three the temporal frequency tuning of both striate and extrastriate cortex is investigated, showing fundamental differences in both tuning characteristics and oscillatory power changes between the two areas. Chapter four introduces the concept of implied-motion and investigates the role of area V5 / MT in the perception of such stimuli and shows, for the first time, the temporal evolution of the response in this area. Similarly a close link is shown between the early evoked potential, produced by the stimulus, and previous BOLD responses. Chapter five investigates the modulation of cortical oscillations to both shifts in attention and varying stimulus contrast. It shows that there are both induced and evoked modulation changes with attention, consistent with areas previously known to show BOLD responses. Chapter six involves a direct comparison of cortical oscillatory changes with those of the BOLD response in relation to the parametric variation of a motion coherence stimulus. It is shown that various cortical areas show a linear BOLD response to motion coherence and, for the first time, that both induced oscillatory and evoked activity also vary linearly in areas coincidental with the BOLD response. The final chapter is a summary of the main conclusions and suggests further work.

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.

Effective electromagnetic noise cancellation with beamformers and synthetic gradiometry in shielded and partly shielded environments

The major challenge of MEG, the inverse problem, is to estimate the very weak primary neuronal currents from the measurements of extracranial magnetic fields. The non-uniqueness of this inverse solution is compounded by the fact that MEG signals contain large environmental and physiological noise that further complicates the problem. In this paper, we evaluate the effectiveness of magnetic noise cancellation by synthetic gradiometers and the beamformer analysis method of synthetic aperture magnetometry (SAM) for source localisation in the presence of large stimulus-generated noise. We demonstrate that activation of primary somatosensory cortex can be accurately identified using SAM despite the presence of significant stimulus-related magnetic interference. This interference was generated by a contact heat evoked potential stimulator (CHEPS), recently developed for thermal pain research, but which to date has not been used in a MEG environment. We also show that in a reduced shielding environment the use of higher order synthetic gradiometry is sufficient to obtain signal-to-noise ratios (SNRs) that allow for accurate localisation of cortical sensory function.

Sensory thresholds obtained from MEG data:cortical psychometric functions

Sensory sensitivity is typically measured using behavioural techniques (psychophysics), which rely on observers responding to very large numbers of stimulus presentations. Psychophysics can be problematic when working with special populations, such as children or clinical patients, because they may lack the compliance or cognitive skills to perform the behavioural tasks. We used an auditory gap-detection paradigm to develop an accurate measure of sensory threshold derived from passively-recorded MEG data. Auditory evoked responses were elicited by silent gaps of varying durations in an on-going noise stimulus. Source modelling was used to spatially filter the MEG data and sigmoidal ‘cortical psychometric functions’ relating response amplitude to gap duration were obtained for each individual participant. Fitting the functions with a curve and estimating the gap duration at which the evoked response exceeded one standard deviation of the prestimulus brain activity provided an excellent prediction of psychophysical threshold. Thus we have demonstrated that accurate sensory thresholds can be reliably extracted from MEG data recorded while participants listen passively to a stimulus. Because we required no behavioural task, the method is suitable for studies of populations where variations in cognitive skills or vigilance make traditional psychophysics unsuitable.

Reflecting on mirror mechanisms:motor resonance effects during action observation only present with low-intensity transcranial magnetic stimulation

Transcranial magnetic stimulation (TMS) studies indicate that the observation of other people's actions influences the excitability of the observer's motor system. Motor evoked potential (MEP) amplitudes typically increase in muscles which would be active during the execution of the observed action. This 'motor resonance' effect is thought to result from activity in mirror neuron regions, which enhance the excitability of the primary motor cortex (M1) via cortico-cortical pathways. The importance of TMS intensity has not yet been recognised in this area of research. Low-intensity TMS predominately activates corticospinal neurons indirectly, whereas high-intensity TMS can directly activate corticospinal axons. This indicates that motor resonance effects should be more prominent when using low-intensity TMS. A related issue is that TMS is typically applied over a single optimal scalp position (OSP) to simultaneously elicit MEPs from several muscles. Whether this confounds results, due to differences in the manner that TMS activates spatially separate cortical representations, has not yet been explored. In the current study, MEP amplitudes, resulting from single-pulse TMS applied over M1, were recorded from the first dorsal interosseous (FDI) and abductor digiti minimi (ADM) muscles during the observation of simple finger abductions. We tested if the TMS intensity (110% vs. 130% resting motor threshold) or stimulating position (FDI-OSP vs. ADM-OSP) influenced the magnitude of the motor resonance effects. Results showed that the MEP facilitation recorded in the FDI muscle during the observation of index-finger abductions was only detected using low-intensity TMS. In contrast, changes in the OSP had a negligible effect on the presence of motor resonance effects in either the FDI or ADM muscles. These findings support the hypothesis that MN activity enhances M1 excitability via cortico-cortical pathways and highlight a methodological framework by which the neural underpinnings of action observation can be further explored. © 2013 Loporto et al.

The role of supraspinal excitability in the development of healthy-limb deficits following anterior cruciate ligament injury

In the current study, we examined how supraspinal and spinal excitability were altered bilaterally after unilateral anterior cruciate ligament reconstruction (ACLr). 7 participants with ACLr and 7 healthy controls underwent transcranial magnetic stimulation (TMS) and electrical stimulation. To evaluate supraspinal excitability, resting motor thresholds (RMT) and motor evoked potential (MEP) stimulus response curves (SRC) were used. To measure spinal excitability, H-reflex SRC gain was assessed. Mixed factorial ANOVAs were used to compare measures between limbs and between groups. Cohen’s d was used to assess effect sizes between groups. Data indicated no significant differences between subject groups or between limbs. However, large effect sizes were found between limbs for H-reflex gain and RMTs suggesting that ACLr can have an effect on some of the variables examined. This study identified decreases in strength in the injured limbs and that subjects with an ACL injury exhibited decreases in spinal and supraspinal excitability of the quadriceps compared to Healthy controls.

Neurorehabilitation of hand functions using brain computer interface

Introduction: Brain computer interface (BCI) is a promising new technology with possible application in neurorehabilitation after spinal cord injury. Movement imagination or attempted movement-based BCI coupled with functional electrical stimulation (FES) enables the simultaneous activation of the motor cortices and the muscles they control. When using the BCI- coupled with FES (known as BCI-FES), the subject activates the motor cortex using attempted movement or movement imagination of a limb. The BCI system detects the motor cortex activation and activates the FES attached to the muscles of the limb the subject is attempting or imaging to move. In this way the afferent and the efferent pathways of the nervous system are simultaneously activated. This simultaneous activation encourages Hebbian type learning which could be beneficial in functional rehabilitation after spinal cord injury (SCI). The FES is already in use in several SCI rehabilitation units but there is currently not enough clinical evidence to support the use of BCI-FES for rehabilitation. Aims: The main aim of this thesis is to assess outcomes in sub-acute tetraplegic patients using BCI-FES for functional hand rehabilitation. In addition, the thesis explores different methods for assessing neurological rehabilitation especially after BCI-FES therapy. The thesis also investigated mental rotation as a possible rehabilitation method in SCI. Methods: Following investigation into applicable methods that can be used to implement rehabilitative BCI, a BCI based on attempted movement was built. Further, the BCI was used to build a BCI-FES system. The BCI-FES system was used to deliver therapy to seven sub-acute tetraplegic patients who were scheduled to receive the therapy over a total period of 20 working days. These seven patients are in a 'BCI-FES' group. Five more patients were also recruited and offered equivalent FES quantity without the BCI. These further five patients are in a 'FES-only' group. Neurological and functional measures were investigated and used to assess both patient groups before and after therapy. Results: The results of the two groups of patients were compared. The patients in the BCI-FES group had better improvements. These improvements were found with outcome measures assessing neurological changes. The neurological changes following the use of the BCI-FES showed that during movement attempt, the activation of the motor cortex areas of the SCI patients became closer to the activation found in healthy individuals. The intensity of the activation and its spatial localisation both improved suggesting desirable cortical reorganisation. Furthermore, the responses of the somatosensory cortex during sensory stimulation were of clear evidence of better improvement in patients who used the BCI-FES. Missing somatosensory evoked potential peaks returned more for the BCI-FES group while there was no overall change in the FES-only group. Although the BCI-FES group had better neurological improvement, they did not show better functional improvement than the FES-only group. This was attributed mainly to the short duration of the study where therapies were only delivered for 20 working days. Conclusions: The results obtained from this study have shown that BCI-FES may induce cortical changes in the desired direction at least faster than FES alone. The observation of better improvement in the patients who used the BCI-FES is a good result in neurorehabilitation and it shows the potential of thought-controlled FES as a neurorehabilitation tool. These results back other studies that have shown the potential of BCI-FES in rehabilitation following neurological injuries that lead to movement impairment. Although the results are promising, further studies are necessary given the small number of subjects in the current study.

Sensory gating and its modulation by cannabinoids: electrophysiological, computational and mathematical analysis

Gating of sensory information can be assessed using an auditory conditioning-test paradigm which measures the reduction in the auditory evoked response to a test stimulus following an initial conditioning stimulus. Recording brainwaves from specific areas of the brain using multiple electrodes is helpful in the study of the neurobiology of sensory gating. In this paper, we use such technology to investigate the role of cannabinoids in sensory gating in the CA3 region of the rat hippocampus. Our experimental results show that application of the exogenous cannabinoid agonist WIN55,212-2 can abolish sensory gating. We have developed a phenomenological model of cannabinoid dynamics incorporated within a spiking neural network model of CA3 with synaptically interacting pyramidal and basket cells. Direct numerical simulations of this model suggest that the basic mechanism for this effect can be traced to the suppression of inhibition of slow GABAB synapses. Furthermore, by working with a simpler mathematical firing rate model we are able to show the robustness of this mechanism for the abolition of sensory gating.

Auditory and visual event-related potential alterations in fragile X syndrome

Le syndrome du X fragile (SXF) est la première cause héréditaire de déficience intellectuelle et également la première cause monogénique d’autisme. Le SXF est causé par l'expansion de la répétition du nucléotide CGG sur le gène FMR1, ce qui empêche l’expression de la protéine FMRP. L’absence du FMRP mène à une altération du développement structurel et fonctionnel de la synapse, ce qui empêche la maturation des synapses induite par l’activité et l’élagage synaptique, qui sont essentiels pour le développement cérébral et cognitif. Nous avons investigué les potentiels reliés aux événements (PRE) évoqués par des stimulations fondamentales auditives et visuelles dans douze adolescents et jeunes adultes (10-22) atteints du SXF, ainsi que des participants contrôles appariés en âge chronologique et développemental. Les résultats indiquent un profil des PRE altéré, notamment l’augmentation de l’amplitude de N1 auditive, par rapport aux deux groupes contrôle, ainsi que l’augmentation des amplitudes de P2 et N2 auditifs et de la latence de N2 auditif. Chez les patients SXF, le traitement sensoriel semble être davantage perturbé qu’immature. En outre, la modalité auditive semble être plus perturbée que la modalité visuelle. En combinaison avec des résultats anatomique du cerveau, des mécanismes biochimiques et du comportement, nos résultats suggèrent une hyperexcitabilité du système nerveux dans le SXF.

Further studies of the visually evoked subcortical potential in man

The Visually Evoked Subcortical Potential, a far-field signal, was originally defined to flash stimulation as a triphasic positive-negative-positive complex with mean latencies of P21 N26.2 P33.6 (Harding and Rubinstein 1980). Inconsistent with its subcortical source however, the signal was found to be tightly localised to the mastoid. This thesis re-examines the earlier protocols using flash stimulation and with auditory masking establishes by topographic studies that the VESP has a widespread scalp distribution, consistent with a far-field source of the signal, and is not a volume-conducted electroretinogram (ERG). Furthermore, mastoid localisation indicates auditory contamination from the click, on discharge of the photostimulator. The use of flash stimulation could not precisely identify the origin of the response. Possible sources of the VESP are the lateral geniculate body (LGB) and the superior colliculus. The LGB received 80% of the nerve fibres from the retina, and responds to high contrast achromatic stimulation in the form of drifting gratings of high spatial frequencies. At low spatial frequencies, it is more sensitive to colour. The superior colliculus is insensitive to colour and suppressed by contrast and responds to transitory rapid movements, and receives about 20% of the optic nerve fibres. A pattern VESP was obtained to black and white checks as a P23.5 N29.2 P34 complex in 93% of normal subjects at an optimal check size of 12'. It was also present as a P23.0 N28.29 P32.23 complex to red and green luminance balanced checks at 2o check size in 73% of subjects. These results were not volume-conducted pattern electroretinogram responses. These findings are consistent with the spatial frequency properties of the lateral geniculate body which is the considered source of the signal. With further work, the VESP may supplement electrodiagnosis of post-chiasmal lesions.

Towards Optimal Testing of Auditory Memory : Methodological development of recording of the mismatch negativity (MMN) of the auditory event-related potential (ERP)

The overlapping sound pressure waves that enter our brain via the ears and auditory nerves must be organized into a coherent percept. Modelling the regularities of the auditory environment and detecting unexpected changes in these regularities, even in the absence of attention, is a necessary prerequisite for orientating towards significant information as well as speech perception and communication, for instance. The processing of auditory information, in particular the detection of changes in the regularities of the auditory input, gives rise to neural activity in the brain that is seen as a mismatch negativity (MMN) response of the event-related potential (ERP) recorded by electroencephalography (EEG). --- As the recording of MMN requires neither a subject s behavioural response nor attention towards the sounds, it can be done even with subjects with problems in communicating or difficulties in performing a discrimination task, for example, from aphasic and comatose patients, newborns, and even fetuses. Thus with MMN one can follow the evolution of central auditory processing from the very early, often critical stages of development, and also in subjects who cannot be examined with the more traditional behavioural measures of auditory discrimination. Indeed, recent studies show that central auditory processing, as indicated by MMN, is affected in different clinical populations, such as schizophrenics, as well as during normal aging and abnormal childhood development. Moreover, the processing of auditory information can be selectively impaired for certain auditory attributes (e.g., sound duration, frequency) and can also depend on the context of the sound changes (e.g., speech or non-speech). Although its advantages over behavioral measures are undeniable, a major obstacle to the larger-scale routine use of the MMN method, especially in clinical settings, is the relatively long duration of its measurement. Typically, approximately 15 minutes of recording time is needed for measuring the MMN for a single auditory attribute. Recording a complete central auditory processing profile consisting of several auditory attributes would thus require from one hour to several hours. In this research, I have contributed to the development of new fast multi-attribute MMN recording paradigms in which several types and magnitudes of sound changes are presented in both speech and non-speech contexts in order to obtain a comprehensive profile of auditory sensory memory and discrimination accuracy in a short measurement time (altogether approximately 15 min for 5 auditory attributes). The speed of the paradigms makes them highly attractive for clinical research, their reliability brings fidelity to longitudinal studies, and the language context is especially suitable for studies on language impairments such as dyslexia and aphasia. In addition I have presented an even more ecological paradigm, and more importantly, an interesting result in view of the theory of MMN where the MMN responses are recorded entirely without a repetitive standard tone. All in all, these paradigms contribute to the development of the theory of auditory perception, and increase the feasibility of MMN recordings in both basic and clinical research. Moreover, they have already proven useful in studying for instance dyslexia, Asperger syndrome and schizophrenia.

Effect of unilateral hearing loss on the speech-evoked auditory brainstem response in the presence of noise

Speech-evoked auditory brainstem responses (ABRs) were acquired in quiet and in the presence of noise at two study sessions to investigate 1) test-retest variability and 2) subcortical representation of speech stimuli. Participants were adults with normal hearing in both ears who listened monaurally and adults with unilateral deafness. Results indicate consistency in responses across sessions and several differences between hearing groups for magnitudes of discrete components.

Analysis of transient otoacoustic emissions and brainstem evoked auditory potentials in neonates with hyperbilirubinemia

A hiperbilirrubinemia é tóxica às vias auditivas e ao sistema nervoso central, deixando sequelas como surdez e encefalopatia. OBJETIVOS: avaliar a audição de neonatos portadores de hiperbilirrubinemia, utilizando-se a pesquisa das emissões otoacústicas evocadas transientes (EOAET) e dos potenciais evocados auditivos do tronco encefálico (PEATE). Estudo prospectivo. CASUÍSTICA E MÉTODOS: Constituíram-se dois grupos: GI (n-25), neonatos com hiperbilirrubinemia; GII (n-22), neonatos sem hiperbilirrubinemia e sem fatores de risco para surdez. Todos os neonatos tinham até 60 dias de vida e foram submetidos à EOAET e ao PEATE. RESULTADOS: 12 neonatos de GI e 10 de GII eram meninas e 13 de GI e 12 de GII eram meninos. As EOAET estavam presentes em todas as crianças, porém com amplitudes menores em GI, especialmente nas frequências de 2 e 3KHz (p < 0,05). No PEATE, observou-se discreto prolongamento de PV e de LI-V em GI. As alterações observadas nesses testes não se correlacionaram aos níveis séricos da bilirrubinemia. CONCLUSÕES: em neonatos portadores de hiperbilirrubinemia, menores amplitudes das EOAET e discreto prolongamento de PV e de LI-V foram constatados indicando comprometimento coclear e retrococlear das vias auditivas, salientando-se a importância da utilização e da interpretação minuciosa de ambos os testes nessas avaliações.