Alpha suppression and connectivity modulations in left temporal and parietal cortices index partial awareness of words

The partial awareness hypothesis is a theoretical proposal that recently provided a reconciling solution to graded and dichotomous accounts of consciousness. It suggests that we can become conscious of distinct properties of an object independently, ranging from low-level features to complex forms of representation. We investigated this hypothesis using classic visual word masking adapted to a near-threshold paradigm. The masking intensity was adjusted to the individual perception threshold, at which individual alphabetical letters, but not words, could be perceived in approximately half of the trials. We confined perception to a pre-lexical stage of word processing that corresponded to a clear condition of partial awareness. At this level of representation, the stimulus properties began to emerge within consciousness, yet they did not escalate to full stimulus awareness. In other words, participants were able to perceive individual letters, while remaining unaware of the whole letter strings presented. Cortical activity measured with MEG was compared between physically identical trials that differed in perception (perceived, not perceived). We found that compared to no awareness, partial awareness of words was characterized by suppression of oscillatory alpha power in left temporal and parietal cortices. The analysis of functional connectivity with seeds based on the power effect in these two regions revealed sparse connections for the parietal seed, and strong connections between the temporal seed and other regions of the language network. We suggest that the engagement of language regions indexed by alpha power suppression is responsible for establishing and maintaining conscious representations of individual pre-lexical units

Quality control of visual gamma oscillation frequency in studies of pharmacology, cognitive neuroscience and large-scale multi-site collaborations

In visual cortex, high-contrast grating stimuli induce neurons to oscillate synchronously with a centre frequency in the gamma range (~30–80 Hz). The peak frequency of visual gamma oscillations is modulated by numerous factors, including stimulus properties, cortical architecture and genetics, however, it can be measured reliably over time. As demonstrated by both animal models and human pharmacological studies, the gamma peak frequency is determined by the excitation/inhibition balance and the time constants of GABAergic processes. This oscillatory parameter could thus reflect inter-individual differences in cortical function/physiology, representing a possible biomarker for pharmacological treatment in conditions such as epilepsy, autism and schizophrenia. This thesis demonstrates the importance of measuring the gamma peak frequency accurately and reliably in magnetoencephalographic (MEG) recordings. In Chapter 2, a novel quality-control (QC) approach was validated for peak frequency estimation and identification of poor-quality data. In Chapter 3, QC of a previous pharmacological MEG study of visual gamma with tiagabine revealed a marked drug-induced reduction of peak frequency. Although contrasting with the null finding originally reported (Muthukumaraswamy et al., 2013), the result is supported by both animal models and recent human studies, demonstrating the potentialities of appropriate QC routines. In Chapter 4, testing for the effect of spatial attention on the gamma peak frequency in primary visual cortex resulted in no evidence of a change. However, the modulation of gamma amplitude by attention was consistent with a role in feed-forward signal propagation across the visual hierarchy. In Chapter 5, the QC approach was used to compare visual gamma data recorded at different sites of the UK MEG Partnership, demonstrating the feasibility of combining data from different MEG systems. These results have implications particularly for pharmacological and large-scale multi-site studies, both of which are emerging as promising approaches for the study of brain function with MEG

Spatial attention modulates visual gamma oscillations across the human ventral stream

Oscillatory synchronization in the gamma frequency range has been proposed as a neuronal mechanism to prioritize processing of relevant stimuli over competing ones. Recent studies in animals found that selective spatial attention enhanced gamma-band synchronization in high-order visual areas (V4) and increased the gamma peak frequency in V1. The existence of such mechanisms in the human visual system is yet to be fully demonstrated. In this study, we used MEG, in combination with an optimised stimulus design, to record visual gamma oscillations from human early visual cortex, while participants performed a visuospatial attention cueing task. First, we reconstructed virtual sensors in V1/V2, where gamma oscillations were strongly induced by visual stimulation alone. Second, following the results of a statistical comparison between conditions of attention, we reconstructed cortical activity also in inferior occipital-temporal regions (V4). The results indicated that gamma amplitude was modulated by spatial attention across the cortical hierarchy, both in the early visual cortex and in higher-order regions of the ventral visual pathway. In contrast, we found no evidence for an increase in the gamma peak frequency in V1/V2 with attention. The gamma response tended to peak earlier in V1/V2 than in V4 by approximately 70 ms, consistent with a feed-forward role of gamma-band activity in propagating sensory representations across the visual cortical hierarchy. Together, these findings suggest that differences in experimental design or methodology can account for the inconsistencies in previous animal and human studies. Furthermore, our results are in line with the hypothesis of enhanced gamma-band synchronization as an attentional mechanism in the human visual cortex

Neurovascular coupling during visual stimulation in Multiple Sclerosis: a MEG-fMRI study

The process of neurovascular coupling ensures that increases in neuronal activity are fed by increases in cerebral blood flow. Evidence suggests that neurovascular coupling may be impaired in multiple sclerosis (MS) due to a combination of brain hypoperfusion, altered cerebrovascular reactivity and oxygen metabolism, and altered levels of vasoactive compounds. Here, we tested the hypothesis that neurovascular coupling is impaired in MS. We characterised neurovascular coupling as the relationship between changes in neuronal oscillatory power within the gamma frequency band (30-80 Hz), as measured by magnetoencephalography (MEG), and associated haemodynamic changes (blood oxygenation level dependent, BOLD, and cerebral blood flow, CBF) as measured by functional MRI. We characterised these responses in the visual cortex in 13 MS patients and in 10 matched healthy controls by using a reversing checkerboard stimulus at five visual contrasts. There were no significant group differences in visual acuity, P100 latencies, occipital grey matter (GM) volumes and baseline CBF. However, in the MS patients we found a significant reduction in peak gamma power, BOLD and CBF responses. There were no significant differences in neurovascular coupling between groups, in the visual cortex. Our results suggest that neuronal and vascular responses are altered in MS. Gamma power reduction could be an indicator of GM dysfunction, possibly mediated by GABAergic changes. Altered hemodynamic responses confirm previous reports of a vascular dysfunction in MS. Despite altered neuronal and vascular responses, neurovascular coupling appears to be preserved in MS, at least within the range of damage and disability studied here

Predicting MEG resting-state functional connectivity using microstructural information

Understanding how human brain microstructure influences functional connectivity is an important endeavor. In this work, magnetic resonance imaging data from ninety healthy participants were used to calculate structural connectivity matrices using the streamline count, fractional anisotropy, radial diffusivity and a myelin measure (derived from multi-component relaxometry) to assign connection strength. Unweighted binarized structural connectivity matrices were also constructed. Magnetoencephalography resting-state data from those participants were used to calculate functional connectivity matrices, via correlations of the Hilbert envelopes of beamformer timeseries in the delta, theta, alpha and beta frequency bands. Non-negative matrix factorization was performed to identify the components of the functional connectivity. Shortest-path-length and search-information analyses of the structural connectomes were used to predict functional connectivity patterns for each participant. The microstructure-informed algorithms predicted the components of the functional connectivity more accurately than they predicted the total functional connectivity. This provides a methodology to understand functional mechanisms better. The shortest-path-length algorithm exhibited the highest prediction accuracy. Of the weights of the structural connectivity matrices, the streamline count and the myelin measure gave the most accurate predictions, while the fractional anisotropy performed poorly. Overall, different structural metrics paint very different pictures of the structural connectome and its relationship to functional connectivity

Significant reductions in human visual gamma frequency by the GABA reuptake inhibitor tiagabine revealed by robust peak frequency estimation

The frequency of visual gamma oscillations is determined by both the neuronal excitation–inhibition balance and the time constants of GABAergic processes. The gamma peak frequency has been linked to sensory processing, cognitive function, cortical structure, and may have a genetic contribution. To disentangle the intricate relationship among these factors, accurate and reliable estimates of peak frequency are required. Here, a bootstrapping approach that provides estimates of peak frequency reliability, thereby increasing the robustness of the inferences made on this parameter was developed. The method using both simulated data and real data from two previous pharmacological MEG studies of visual gamma with alcohol and tiagabine was validated. In particular, the study by Muthukumaraswamy et al. [2013a] (Neuropsychopharmacology 38(6):1105–1112), in which GABAergic enhancement by tiagabine had previously demonstrated a null effect on visual gamma oscillations, contrasting with strong evidence from both animal models and very recent human studies was re-evaluated. After improved peak frequency estimation and additional exclusion of unreliably measured data, it was found that the GABA reuptake inhibitor tiagabine did produce, as predicted, a marked decrease in visual gamma oscillation frequency. This result demonstrates the potential impact of objective approaches to data quality control, and provides additional translational evidence for the mechanisms of GABAergic transmission generating gamma oscillations in humans

Attenuated post-movement beta rebound associated with schizotypal features in healthy people

Introduction: Schizophrenia and Schizotypal Personality Disorder (SPD) lie on a single spectrum of mental illness and converging evidence suggests similarities in the etiology of the two conditions. However, schizotypy is a heterogeneous facet of personality in the healthy population and so may be seen as a bridge between health and mental illness. Neural evidence for such a continuity would have implications for the characterization and treatment of schizophrenia. Based on our previous work identifying a relationship between symptomology in Schizophrenia and abnormal movement-induced electrophysiological response (the post-movement beta rebound (PMBR)), we predicted that if subclinical schizotypy arises from similar neural mechanisms to schizophrenia, schizotypy in healthy individuals would be associated with reduced PMBR. Methods: 116 participants completed a visuomotor task whilst their neural activity was recorded by magnetoencephalography. Partial correlations were computed between a measure of PMBR extracted from left primary motor cortex and scores on the Schizotypal Personality Questionnaire (SPQ), a self-report measure of schizotypal personality. Correlations between PMBR and SPQ factor scores measuring Cognitive-Perceptual, Interpersonal and Disorganization dimensions of schizotypy were also computed. Effects of site, age, and sex were controlled for. Results: We found a significant negative correlation between total SPQ score and PMBR. This was most strongly mediated by variance shared between Interpersonal and Disorganization factor scores. Conclusion: These findings indicate a continuum of neural deficit between schizotypy and schizophrenia, with diminution of PMBR, previously reported in schizophrenia, also measurable in individuals with schizotypal features, particularly disorganization and impaired interpersonal relations

Electrophysiological network alterations in adults with copy number variants associated with high neurodevelopmental risk

Rare copy number variants associated with increased risk for neurodevelopmental and psychiatric disorders (referred to as ND-CNVs) are characterized by heterogeneous phenotypes thought to share a considerable degree of overlap. Altered neural integration has often been linked to psychopathology and is a candidate marker for potential convergent mechanisms through which ND-CNVs modify risk; however, the rarity of ND-CNVs means that few studies have assessed their neural correlates. Here, we used magnetoencephalography (MEG) to investigate resting-state oscillatory connectivity in a cohort of 42 adults with ND-CNVs, including deletions or duplications at 22q11.2, 15q11.2, 15q13.3, 16p11.2, 17q12, 1q21.1, 3q29, and 2p16.3, and 42 controls. We observed decreased connectivity between occipital, temporal and parietal areas in participants with ND-CNVs. This pattern was common across genotypes and not exclusively characteristic of 22q11.2 deletions, which were present in a third of our cohort. Furthermore, a data-driven graph theory framework enabled us to successfully distinguish participants with ND-CNVs from unaffected controls using differences in node centrality and network segregation. Together, our results point to alterations in electrophysiological connectivity as a putative common mechanism through which genetic factors confer increased risk for neurodevelopmental and psychiatric disorders

Attenuated post-movement beta rebound associated with schizotypal features in healthy people

Introduction: Schizophrenia and Schizotypal Personality Disorder (SPD) lie on a single spectrum of mental illness and converging evidence suggests similarities in the etiology of the two conditions. However, schizotypy is a heterogeneous facet of personality in the healthy population and so may be seen as a bridge between health and mental illness. Neural evidence for such a continuity would have implications for the characterization and treatment of schizophrenia. Based on our previous work identifying a relationship between symptomology in Schizophrenia and abnormal movement-induced electrophysiological response (the post-movement beta rebound (PMBR)), we predicted that if subclinical schizotypy arises from similar neural mechanisms to schizophrenia, schizotypy in healthy individuals would be associated with reduced PMBR. Methods: 116 participants completed a visuomotor task whilst their neural activity was recorded by magnetoencephalography. Partial correlations were computed between a measure of PMBR extracted from left primary motor cortex and scores on the Schizotypal Personality Questionnaire (SPQ), a self-report measure of schizotypal personality. Correlations between PMBR and SPQ factor scores measuring Cognitive-Perceptual, Interpersonal and Disorganization dimensions of schizotypy were also computed. Effects of site, age, and sex were controlled for. Results: We found a significant negative correlation between total SPQ score and PMBR. This was most strongly mediated by variance shared between Interpersonal and Disorganization factor scores. Conclusion: These findings indicate a continuum of neural deficit between schizotypy and schizophrenia, with diminution of PMBR, previously reported in schizophrenia, also measurable in individuals with schizotypal features, particularly disorganization and impaired interpersonal relations