Causal roles of neural synchrony in signal transmission and cognition in the human brain

Healthy cognition depends on our capacity to influence the processing of external sensory events from our environment by expectations, previous experience and internal goals. In the brain, this is reflected in finely tuned interactions between higher-order frontal and parietal areas that take "top-down" cognitive control over sensory processing via influencing "bottom-up"-driven lower-level sensory regions. While brain regions that underlie top-down control are well defined anatomically, it is still an open question how the bidirectional communication between these brain regions and sensory areas is organized. In animal models, temporally correlated neuronal activity, i.e., neuronal synchronization, has been proposed to coordinate anatomically distributed processing and to regulate feedback control over the feedforward flow of sensory information in different frequency channels. However, there is only scarce evidence to support this hypothesis in the human brain and there is a need for multimodal neuroimaging techniques that would allow both whole brain mapping of large-scale brain networks and studying their causal role.

We will use state-of-the art multimodal neuroimaging with combined magneto/ electroencephalography (MEG-EEG) and combined transcranial magnetic stimulation/ electroencephalography (TMS-EEG) to unravel the mechanistic / causal role of network interactions in achieving the internally controlled regulation of bottom-up (visual) signalling. We will identify interactions by which the attentional frontal and parietal brain areas influence the excitability and timing of neuronal activity in visual areas for the selection of information in accordance with expectations and relevance for current behavioural goals. Our overarching aim is to study how these top-down interactions are achieved in the human brain and to develop new probes of network integrity in the human brain.

Exploiting cutting-edge analyses techniques for MEG-EEG data acquired during tasks engaging top-down control, we will uncover the dynamic nature and cortical sources of the large-scale network interactions that are correlated with feedback control of visual processing, and their local consequences on visual cortex activity. Based on these individual dynamic networks obtained from MEG-EEG, we will test how activity induced by non-invasive brain stimulation with single-pulse TMS propagates through the brain as a function of areas being stimulated and its dominant frequency. To this end, we will use simultaneous EEG recordings (TMS-EEG) and the same cutting-edge analysis framework for measuring network interactions in MEG-EEG, allowing to integrate these approaches offline in the same participants (MEG-EEG-TMS). Finally, we will use rhythmic TMS at natural frequencies to emulate top-down effects. Using simultaneous EEG and by means of integration with the MEG-EEG data, we will test to what extent the TMS-emulated top-down effects depend on the importance of the targeted brain region in the network (its "hubness") and are state-dependent.

Collectively, our project will reveal both whole-brain correlative (MEG-EEG) and mechanistic (TMS-EEG) insight into the functional significance of large-scale neural synchronization in implementing top-down control of feedforward signalling and visual processing. The project is also expected to demonstrate the utility of MEG/EEG-guided TMS for improving the efficacy of repetitive TMS, which is widely used in cognitive and clinical neuroscience. Revealing whether TMS efficacy depends on network parameters in individual participants has important implications for its use in experimental and clinical settings. Altogether, this project will therefore help to identify the basic electrophysiological building blocks of brain network interactions, and to advance the tools for studying and modulating these processes.

Flexible cognition depends on finely tuned communication between brain regions in large-scale brain networks. Local field potentials in non-human primates have revealed specific frequency channels that exert feedforward and feedback control of sensory processing through synchronization of oscillatory neuronal activity. However, little is known about these processes in the human brain.

Our objective is to unravel the causal/mechanistic role of large-scale network synchronization, i.e. oscillatory phase-coupling, in orchestrating feedback and feedforward signal transmission and cognitive operations in humans. We will use (1) magneto- and electroencephalography (MEG-EEG) combined with cutting-edge analysis techniques to establish (a) the nature of large-scale network interactions associated with top-down control in the attention system, (b) their effect on local neural activity in visual cortex and (c) on visual task performance. Using the same analysis framework, we will integrate these data with combined transcranial magnetic stimulation/electroencephalography (TMS-EEG) in the same sample to (2) test the hypothesis that directionality of communication depends on frequency of the channel by investigating the spreading of activity induced by single-pulse TMS. Finally, we will (3) study by TMS-EEG the extent to which emulation of top-down effects by frequency-tuned rhythmic TMS relates to interindividual variability in MEG-derived hubness of frontal and parietal areas.

The analysis in a common framework will allow the offline integration of all techniques (multimodal MEG-EEG-TMS) in the same sample. This will establish if the large-scale networks of top-down control play a causal (vs. correlative) role in network communication influencing perception. It will also advance our understanding of the physiological factors underlying variability in TMS outcome, with implications for experimental and therapeutic control of brain oscillations and functions by TMS.

Beneficiaries will be researchers in fundamental and clinical neuroscience, experimental psychology and medical staff. Possible secondary beneficiaries are the elderly and clinical patient population.

We will develop new methods for measuring brain network integrity in human participants. This will allow to unravel the fundamental building blocks of brain network interactions for a better understanding of how brain activity is organized to bring about complex mental functions. This has broad implications for the understanding of the normal brain, the impaired brain, and for systems neuroscience, namely how assemblies of network elements communicate, and how this communication may be emulated by interventions.

A detailed understanding of these mechanisms is fundamental for developing tests and treatment in patient with neurological or psychiatric deficits. Development of new tools for measuring brain connectivity should bring new clinical opportunities. For instance, tests of network connectivity could be used for stratification of patients as to the level of network dysfunction, prognosis, treatment outcome etc. Applications in many patient groups are envisagable given that many neurologic and psychiatric conditions have been associated with dysfunctional connectivity.

We will adopt the following strategies to optimize impact.

We are regularly invited to give presentation of our research not only to specialized audiences but also to large interdisciplinary audiences, and publish our work in high-impact journals that reach a wide readership (e.g. Current Biology, Plos Biology, Neuron, Trends in Cognitive Sciences, Trends in Neuroscience), alongside more specialized journals (e.g. Journal of Neuroscience, NeuroImage, Cerebral Cortex, Psychological Science).

We are working closely with clinical colleagues for creating new interdisciplinary ties within Glasgow University and affiliated Hospitals (such as the South Glasgow University Hospital) to disseminate our results and for exchange. We also exchange regularly with the private commercial sector (biomedical companies). We will use these ties to promote clinical opportunities of our findings, namely to translate our results into clinical trials and possibly into clinical practice.

We also seek to engage with the wider public by various means. We make use of established links (e.g. Brain Awareness Week by the Dana Foundation; Glasgow Science Centre; British Science Festival of the British Science Association), and seek advice for the broadest and impactful dissemination of our results from the press office of Glasgow University and the User Engagement Officer of our School. This officer advises staff about specific links with industry and the media, in addition to constantly seeking out new ways to promote engagement.

Our research has impact on training nationally and internationally through workshops and summer/autumn schools, where we regularly present our most recent findings among new generations of neuroscientists and medical staff. Our research has also impact on policy recommendation papers (some of our work has informed the report of the Nuffield council of Bioethics on "Intervening in the brain", setting out an ethical framework to guide the practices of those involved in development, regulation, use and promotion of novel neuro-technologies). This will ensure effective and appropriate dissemination and exploitation of the results to provide maximum benefit and impact.