A multimodal perspective on the composition of cortical oscillations:frontiers in human neuroscience

An expanding corpus of research details the relationship between functional magnetic resonance imaging (fMRI) measures and neuronal network oscillations. Typically, integratedelectroencephalography(EEG) and fMRI,orparallel magnetoencephalography (MEG) and fMRI are used to draw inference about the consanguinity of BOLD and electrical measurements. However, there is a relative dearth of information about the relationship between E/MEG and the focal networks from which these signals emanate. Consequently, the genesis and composition of E/MEG oscillations requires further clarification. Here we aim to contribute to understanding through a series of parallel measurements of primary motor cortex (M1) oscillations, using human MEG and in-vitro rodent local field potentials. We compare spontaneous activity in the ~10Hz mu and 15-30Hz beta frequency ranges and compare MEG signals with independent and integrated layers III and V(LIII/LV) from in vitro recordings. We explore the mechanisms of oscillatory generation, using specific pharmacological modulation with the GABA-A alpha-1 subunit modulator zolpidem. Finally, to determine the contribution of cortico-cortical connectivity, we recorded in-vitro M1, during an incision to sever lateral connections between M1 and S1 cortices. We demonstrate that frequency distribution of MEG signals appear have closer statistically similarity with signals from integrated rather than independent LIII/LV laminae. GABAergic modulation in both modalities elicited comparable changes in the power of the beta band. Finally, cortico-cortical connectivity in sensorimotor cortex (SMC) appears to directly influence the power of the mu rhythm in LIII. These findings suggest that the MEG signal is an amalgam of outputs from LIII and LV, that multiple frequencies can arise from the same cortical area and that in vitro and MEG M1 oscillations are driven by comparable mechanisms. Finally, corticocortical connectivity is reflected in the power of the SMC mu rhythm. © 2013 Ronnqvist, Mcallister, Woodhall, Stanford and Hall.

Causality and synchronisation in complex systems with applications to neuroscience

This thesis presents an investigation, of synchronisation and causality, motivated by problems in computational neuroscience. The thesis addresses both theoretical and practical signal processing issues regarding the estimation of interdependence from a set of multivariate data generated by a complex underlying dynamical system. This topic is driven by a series of problems in neuroscience, which represents the principal background motive behind the material in this work. The underlying system is the human brain and the generative process of the data is based on modern electromagnetic neuroimaging methods . In this thesis, the underlying functional of the brain mechanisms are derived from the recent mathematical formalism of dynamical systems in complex networks. This is justified principally on the grounds of the complex hierarchical and multiscale nature of the brain and it offers new methods of analysis to model its emergent phenomena. A fundamental approach to study the neural activity is to investigate the connectivity pattern developed by the brain’s complex network. Three types of connectivity are important to study: 1) anatomical connectivity refering to the physical links forming the topology of the brain network; 2) effective connectivity concerning with the way the neural elements communicate with each other using the brain’s anatomical structure, through phenomena of synchronisation and information transfer; 3) functional connectivity, presenting an epistemic concept which alludes to the interdependence between data measured from the brain network. The main contribution of this thesis is to present, apply and discuss novel algorithms of functional connectivities, which are designed to extract different specific aspects of interaction between the underlying generators of the data. Firstly, a univariate statistic is developed to allow for indirect assessment of synchronisation in the local network from a single time series. This approach is useful in inferring the coupling as in a local cortical area as observed by a single measurement electrode. Secondly, different existing methods of phase synchronisation are considered from the perspective of experimental data analysis and inference of coupling from observed data. These methods are designed to address the estimation of medium to long range connectivity and their differences are particularly relevant in the context of volume conduction, that is known to produce spurious detections of connectivity. Finally, an asymmetric temporal metric is introduced in order to detect the direction of the coupling between different regions of the brain. The method developed in this thesis is based on a machine learning extensions of the well known concept of Granger causality. The thesis discussion is developed alongside examples of synthetic and experimental real data. The synthetic data are simulations of complex dynamical systems with the intention to mimic the behaviour of simple cortical neural assemblies. They are helpful to test the techniques developed in this thesis. The real datasets are provided to illustrate the problem of brain connectivity in the case of important neurological disorders such as Epilepsy and Parkinson’s disease. The methods of functional connectivity in this thesis are applied to intracranial EEG recordings in order to extract features, which characterize underlying spatiotemporal dynamics before during and after an epileptic seizure and predict seizure location and onset prior to conventional electrographic signs. The methodology is also applied to a MEG dataset containing healthy, Parkinson’s and dementia subjects with the scope of distinguishing patterns of pathological from physiological connectivity.

Investigating the functional properties of the somatosensory cortex during experimental visceral pain using magnetoencephalography

Background The somatosensory cortex has been inconsistently activated in pain studies and the functional properties of subregions within this cortical area are poorly understood. To address this we used magnetoencephalography (MEG), a brain imaging technique capable of recording changes in cortical neural activity in real-time, to investigate the functional properties of the somatosensory cortex during different phases of the visceral pain experience. Methods In eight participants (4 male), 151-channel whole cortex MEG was used to detect cortical neural activity during 25 trials lasting 20 seconds each. Each trial comprised four separate periods of 5 seconds in duration. During each of the periods, different visual cues were presented, indicating that period 1=rest, period 2=anticipation, period 3=pain and period 4=post pain. During period 3, participants received painful oesophageal balloon distensions (four at 1 Hz). Regions of cortical activity were identified using Synthetic Aperture Magnetometry (SAM) and by the placement of virtual electrodes in regions of interest within the somatosensory cortex, time-frequency wavelet plots were generated. Results SAM analysis revealed significant activation with the primary (S1) and secondary (S2) somatosensory cortices. The time-frequency wavelet spectrograms showed that activation in S1 increased during the anticipation phase and continued during the presentation of the stimulus. In S2, activation was tightly time and phase-locked to the stimulus within the pain period. Activations in both regions predominantly occurred within the 10–15 Hz and 20–30 Hz frequency bandwidths. Discussion These data are consistent with the role of S1 and S2 in the sensory discriminatory aspects of pain processing. Activation of S1 during anticipation and then pain may be linked to its proposed role in attentional as well as sensory processing. The stimulus-related phasic activity seen in S2 demonstrates that this region predominantly encodes information pertaining to the nature and intensity of the stimulus.

Optic flow in human vision: MEG reveals a foveo-fugal bias in V1, specialization for spiral space in hMSTs, and global motion sensitivity in the IPS

Abstract We recorded MEG responses from 17 participants viewing random-dot patterns simulating global optic flow components (expansion, contraction, rotation, deformation, and translation) and a random motion control condition. Theta-band (3–7 Hz), MEG signal power was greater for expansion than the other optic flow components in a region concentrated along the calcarine sulcus, indicating an ecologically valid, foveo-fugal bias for unidirectional motion sensors in V1. When the responses to the optic flow components were combined, a decrease in MEG beta-band (17–23 Hz) power was found in regions extending beyond the calcarine sulcus to the posterior parietal lobe (inferior to IPS), indicating the importance of structured motion in this region. However, only one cortical area, within or near the V5/hMT+ complex, responded to all three spiral-space components (expansion, contraction, and rotation) and showed no selectivity for global translation or deformation: we term this area hMSTs. This is the first demonstration of an exclusive region for spiral space in the human brain and suggests a functional role better suited to preliminary analysis of ego-motion than surface pose, which would involve deformation. We also observed that the rotation condition activated the cerebellum, suggesting its involvement in visually mediated control of postural adjustment.

Functional neuroimaging and behavioural studies on global form processing in the human visual system

Magnetoencephalography (MEG), functional magnetic resonance imaging (fMRI) and behavioural experiments were used to investigate the neural processes underlying global form perception in human vision. Behavioural studies using Glass patterns examined sensitivity for detecting radial, rotational and horizontal structure. Neuroimaging experiments using either Glass patterns or arrays of Gabor patches determined the spatio-temporal neural responseto global form. MEG data were analysed using synthetic aperture magnetometry (SAM) to spatially map event-related cortical oscillatory power changes: the temporal sequencing of activity within a discrete cortical area was determined using a Morlet wavelet transform. A case study was conducted to determine the effects of strbismic amblyopia on global form processing: all other observers were normally-sighted. The main findings from normally-sighted observers were: 1) sensitivity to horizontal structure was less than for radial or rotational structure; 2) the neural response to global structure was a reduction in cortical oscillatory power (10-30 Hz) within a network of extrastriate areas, including V4 and V3a; 3) the extend of reduced cortical power was least for horizontal patters; 4) V1 was not identified as a region of peak activity with either MEG or fMRI. The main findings with the strabismic amblyope were: 1) sensitivity for detection of radial, rotational, and horizontal structure was reduced when viewed with the amblyopic- relative to the fellow- eye; 2) cortical power changes within V4 to the presentation of rotational Glass patterns were less when viewed with the amblyopic- compared with the fellow- eye. The main conclusions are: 1) a network of extrastriate cortical areas are involved in the analysis of global form, with the most prominent change in neural activity being a reduction in oscillatory power within the 10-30 Hz band; 2) in strabismic amblyopia, the neuronal assembly associated with form perception in extrastriate cortex may be dysfunctional, the nature of this dysfunction may be a change in the normal temporal pattern of neuronal discharges; 3) MEG, fMRI and behavioural measures support the notion that different neural processes underlie the perception of horizontal as opposed to radial or rotational structure.

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.

Pathological changes in the primary visual cortex (Area V1) in Creutzfeldt-Jakob syndrome

About 10% of patients with Creutzfeldt-Jakob syndrome (disease) (CJD) exhibit visual symptoms at presentation and approximately 50% during the course of the disease. The objectives of the present study were to determine, in two subtypes of CJD, viz., sporadic CJD (sCJD) and variant CJD (vCJD), the degree of pathological change in the primary visual cortex (area V1) and the extent to which pathology in V1 may influence visual function. The vacuolation (‘spongiform change’), surviving neurons, glial cell nuclei, and deposits of prion protein (PrP) were quantified in V1 obtained post-mortem in nine cases of sCJD and eleven cases of vCJD. In sCJD, the vacuoles and PrP deposits were regularly distributed along the cortex parallel to the pia mater in clusters with a mean dimension from 450 to 1000 µm. Across the cortex, the vacuolation was most severe in laminae II/III and the glial cell reaction in laminae V/VI. Surviving neurons were most abundant in laminae II/III while PrP deposition either affected all laminae equally or was maximal in lamina II/III. In vCJD, the vacuoles and diffuse PrP deposits were distributed relatively uniformly parallel to the pia mater while the florid deposits were consistently distributed in regular clusters. Across V1, the vacuoles either exhibited a bimodal distribution or were uniformly distributed. The diffuse PrP deposits occurred most frequently in laminae II/III while the florid deposits were more generally distributed. The data suggest that in both sCJD and vCJD, pathological changes in area V1 may affect the processing of visual information in laminae II/III and its transmission from V1 to V2 and to subcortical visual areas. In addition, the data suggest an association in sCJD between the developing pathology and the functional domains of V1 while in vCJD the pathology is more uniformly distributed. These changes could be a factor in the development of poor visual acuity, visual field defects, cortical blindness, diplopia, and vertical gaze palsy that have been observed in Creutzfeldt-Jakob syndrome.

Pathological changes in the primary visual cortex (area V1) in sporadic Creutzfeldt-Jakob disease

Purpose. To determine the degree of pathological change in the primary visual cortex (area V1) in patients with Creutzfeldt-Jakob disease. Method. The vacuolation, surviving neurons, glial cells, and deposits of prion protein were quantified in area V1 obtained postmortem in nine cases of the sporadic type of Creutzfeldt-Jakob disease. Results. Variations in the density of glial cells and in prion protein deposition were particularly evident between patients. In the upper and lower cortical laminae, vacuoles and prion protein deposits were regularly distributed in clusters with a mean dimensions of 450 to 1000 µm. Vacuolation in area V1 was most severe in lamina III and the glial cell reaction in lamina V or VI. Surviving neurons were most abundant in lamina II or III, whereas prion protein deposition either affected all laminae equally or was maximal in lamina II or III. Conclusion. The data suggest that pathological changes in area V1 in sporadic type of Creutzfeldt-Jakob disease may affect the transmission of visual information from area V1 to V2 and to subcortical visual areas. In addition, the data suggest an association between the developing pathology and the functional domains of area V1.

Does the neurodegeneration of Alzheimer’s disease spread between visual cortical regions B17 and B18 via the feedforward or feedback short cortico-cortical projections?

The laminar distribution of senile plaques (SP) and neurofibrillary tangles (NFT) was studied in areas B17 and B18 of the visual cortex in 18 cases of Alzheimer’s disease which varied in disease onset and duration. The objective was to test the hypothesis that SP and NFT could spread via either the feedforward or feedback short cortico-cortical projections. In area B17, the mean density of SP and NFT reached a maximum in lamina III and in laminae II and III respectively. In B18, mean SP density was maximal in laminae III and IV and NFT density in laminae II and III. No significant correlations were observed in any cortical lamina between the density of SP and patient age. However, the density of NFT in laminae III, IV and VI in B18 was negatively correlated with patient age. In addition, in B18, the density of SP in lamina II and lamina V was negatively correlated with disease duration and disease onset respectively. Although these results suggest that SP and NFT might spread between B17 and B18 via the feedforward short cortico-cortical projections, it is also possible that the longer cortico-cortical and cortico-subcortical connections may be involved.

Magnetoencephalography:technical improvements in image co-registration and studies of visual cortical oscillations

The work presented in this thesis is divided into two distinct sections. In the first, the functional neuroimaging technique of Magnetoencephalography (MEG) is described and a new technique is introduced for accurate combination of MEG and MRI co-ordinate systems. In the second part of this thesis, MEG and the analysis technique of SAM are used to investigate responses of the visual system in the context of functional specialisation within the visual cortex. In chapter one, the sources of MEG signals are described, followed by a brief description of the necessary instrumentation for accurate MEG recordings. This chapter is concluded by introducing the forward and inverse problems of MEG, techniques to solve the inverse problem, and a comparison of MEG with other neuroimaging techniques. Chapter two provides an important contribution to the field of research with MEG. Firstly, it is described how MEG and MRI co-ordinate systems are combined for localisation and visualisation of activated brain regions. A previously used co-registration methods is then described, and a new technique is introduced. In a series of experiments, it is demonstrated that using fixed fiducial points provides a considerable improvement in the accuracy and reliability of co-registration. Chapter three introduces the visual system starting from the retina and ending with the higher visual rates. The functions of the magnocellular and the parvocellular pathways are described and it is shown how the parallel visual pathways remain segregated throughout the visual system. The structural and functional organisation of the visual cortex is then described. Chapter four presents strong evidence in favour of the link between conscious experience and synchronised brain activity. The spatiotemporal responses of the visual cortex are measured in response to specific gratings. It is shown that stimuli that induce visual discomfort and visual illusions share their physical properties with those that induce highly synchronised gamma frequency oscillations in the primary visual cortex. Finally chapter five is concerned with localization of colour in the visual cortex. In this first ever use of Synthetic Aperture Magnetometry to investigate colour processing in the visual cortex, it is shown that in response to isoluminant chromatic gratings, the highest magnitude of cortical activity arise from area V2.

Cortical activity during rotational and linear transformations

Neuroimaging studies of cortical activation during image transformation tasks have shown that mental rotation may rely on similar brain regions as those underlying visual perceptual mechanisms. The V5 complex, which is specialised for visual motion, is one region that has been implicated. We used functional magnetic resonance imaging (fMRI) to investigate rotational and linear transformation of stimuli. Areas of significant brain activation were identified for each of the primary mental transformation tasks in contrast to its own perceptual reference task which was cognitively matched in all respects except for the variable of interest. Analysis of group data for perception of rotational and linear motion showed activation in areas corresponding to V5 as defined in earlier studies. Both rotational and linear mental transformations activated Brodman Area (BA) 19 but did not activate V5. An area within the inferior temporal gyrus, representing an inferior satellite area of V5, was activated by both the rotational perception and rotational transformation tasks, but showed no activation in response to linear motion perception or transformation. The findings demonstrate the extent to which neural substrates for image transformation and perception overlap and are distinct as well as revealing functional specialisation within perception and transformation processing systems.

BMI not WHR modulates BOLD fMRI responses in a sub-cortical reward network when participants judge the attractiveness of human female bodies

In perceptual terms, the human body is a complex 3d shape which has to be interpreted by the observer to judge its attractiveness. Both body mass and shape have been suggested as strong predictors of female attractiveness. Normally body mass and shape co-vary, and it is difficult to differentiate their separate effects. A recent study suggested that altering body mass does not modulate activity in the reward mechanisms of the brain, but shape does. However, using computer generated female body-shaped greyscale images, based on a Principal Component Analysis of female bodies, we were able to construct images which covary with real female body mass (indexed with BMI) and not with body shape (indexed with WHR), and vice versa. Twelve observers (6 male and 6 female) rated these images for attractiveness during an fMRI study. The attractiveness ratings were correlated with changes in BMI and not WHR. Our primary fMRI results demonstrated that in addition to activation in higher visual areas (such as the extrastriate body area), changing BMI also modulated activity in the caudate nucleus, and other parts of the brain reward system. This shows that BMI, not WHR, modulates reward mechanisms in the brain and we infer that this may have important implications for judgements of ideal body size in eating disordered individuals.

Cortical dynamics and synchronization related to multiple target consolidation under rapid-serial-visual-presentation conditions

The present report reviews behavioural, electroencephalographic, and especially magnetoencephalographic findings on the cortical mechanisms underlying attentional processes that separate targets from distractors and that ensure durable target representations for goal-directed action. A common way of investigation is to observe the system’s overt and covert behaviour when capacity limitations are reached. Here we focus on the aspect of temporally enhanced processing load, namely on performance deficits occurring under rapid-serial-visual-presentation (RSVP) conditions. The most prominent of these deficits is the so-called “attentional blink” (AB) effect. We first report MEG findings with respect to the time course of activation that shows modulations around 300 ms after target onset which reflect demands and success of target consolidation. Then, findings regarding long-range inter-area phase synchronization are reported that are hypothesized to mediate communication within the attentional network. Changes in synchronization reflect changes in the attentional demands of the task and are directly related to behavioural performance. Furthermore, enhanced vigilance of the system elicits systematically increased synchronization indices. A hypothetical framework is sketched out that aims at explaining limitations in multiple target consolidation under RSVP conditions.

Cortical mechanisms of attention in time:neural correlates of the Lag-1-sparing phenomenon

If humans monitor streams of rapidly presented (approximately 100-ms intervals) visual stimuli, which are typically specific single letters of the alphabet, for two targets (T1 and T2), they often miss T2 if it follows T1 within an interval of 200-500 ms. If T2 follows T1 directly (within 100 ms; described as occurring at 'Lag 1'), however, performance is often excellent: the so-called 'Lag-1 sparing' phenomenon. Lag-1 sparing might result from the integration of the two targets into the same 'event representation', which fits with the observation that sparing is often accompanied by a loss of T1-T2 order information. Alternatively, this might point to competition between the two targets (implying a trade-off between performance on T1 and T2) and Lag-1 sparing might solely emerge from conditional data analysis (i.e. T2 performance given T1 correct). We investigated the neural correlates of Lag-1 sparing by carrying out magnetoencephalography (MEG) recordings during an attentional blink (AB) task, by presenting two targets with a temporal lag of either 1 or 2 and, in the case of Lag 2, with a nontarget or a blank intervening between T1 and T2. In contrast to Lag 2, where two distinct neural responses were observed, at Lag 1 the two targets produced one common neural response in the left temporo-parieto-frontal (TPF) area but not in the right TPF or prefrontal areas. We discuss the implications of this result with respect to competition and integration hypotheses, and with respect to the different functional roles of the cortical areas considered. We suggest that more than one target can be identified in parallel in left TPF, at least in the absence of intervening nontarget information (i.e. masks), yet identified targets are processed and consolidated as two separate events by other cortical areas (right TPF and PFC, respectively).

Neurophysiological evaluation of convergent afferents innervating the human esophagus and area of referred pain on the anterior chest wall

Noxious stimuli in the esophagus cause pain that is referred to the anterior chest wall because of convergence of visceral and somatic afferents within the spinal cord. We sought to characterize the neurophysiological responses of these convergent spinal pain pathways in humans by studying 12 healthy subjects over three visits (V1, V2, and V3). Esophageal pain thresholds (Eso-PT) were assessed by electrical stimulation and anterior chest wall pain thresholds (ACW-PT) by use of a contact heat thermode. Esophageal evoked potentials (EEP) were recorded from the vertex following 200 electrical stimuli, and anterior chest wall evoked potentials (ACWEP) were recorded following 40 heat pulses. The fear of pain questionnaire (FPQ) was administered on V1. Statistical data are shown as point estimates of difference +/- 95% confidence interval. Pain thresholds increased between V1 and V3 [Eso-PT: V1-V3 = -17.9 mA (-27.9, -7.9) P < 0.001; ACW-PT: V1-V3 = -3.38 degrees C (-5.33, -1.42) P = 0.001]. The morphology of cortical responses from both sites was consistent and equivalent [P1, N1, P2, N2 complex, where P1 and P2 are is the first and second positive (downward) components of the CEP waveform, respectively, and N1 and N2 are the first and second negative (upward) components, respectively], indicating activation of similar cortical networks. For EEP, N1 and P2 latencies decreased between V1 and V3 [N1: V1-V3 = 13.7 (1.8, 25.4) P = 0.02; P2: V1-V3 = 32.5 (11.7, 53.2) P = 0.003], whereas amplitudes did not differ. For ACWEP, P2 latency increased between V1 and V3 [-35.9 (-60, -11.8) P = 0.005] and amplitudes decreased [P1-N1: V1-V3 = 5.4 (2.4, 8.4) P = 0.01; P2-N2: 6.8 (3.4, 10.3) P < 0.001]. The mean P1 latency of EEP over three visits was 126.6 ms and that of ACWEP was 101.6 ms, reflecting afferent transmission via Adelta fibers. There was a significant negative correlation between FPQ scores and Eso-PT on V1 (r = -0.57, P = 0.05). These data provide the first neurophysiological evidence of convergent esophageal and somatic pain pathways in humans.