Multi-modal dissection of neural circuits in health and disease
Lead Research Organisation:
King's College London
Department Name: Forensic and Neurodevelopmental Science
Abstract
How does our brain generate and control our emotions, cognition and behaviour? How does brain activity change across the lifespan and in disease? Understanding the neural basis of brain functioning requires knowledge about the spatial and temporal aspects of information processing. Electrophysiology and functional magnetic resonance imaging (fMRI) are two techniques widely used to investigate brain function. However, neither of these technologies alone can provide the information necessary to understand the spatiotemporal aspects of information processing in the brain. Electrophysiology is a "gold standard" in direct measurement of neural activity, with excellent temporal resolution and precision. It can inform about the directionality of information flow, but it has limited spatial coverage, overlooking system-wide dynamics. fMRI, on the other hand, has a good spatial resolution but is an indirect measure of neural activity with low temporal resolution, and no good way to determine the directionality of the information flow in the brain. Simultaneous measurement of electrophysiology and fMRI signals thus emerges as a natural consequence of the complementarity between their temporal and spatial resolutions and the origin of their sources. Furthermore, simultaneous recordings in the same animal eliminate physiological variations, environmental influences, variance in sensory stimulation, and reduce the experimental time. Most importantly, during simultaneous recording, the same neural activity contributes to the electrophysiology and fMRI data thus allowing causal, and not just correlational relationships, to be obtained.
Such an approach has proven valuable in elucidating the neural basis of the blood oxygenation level dependant (BOLD) fMRI signal. The combination of electroencephalography (EEG) and fMRI is increasingly used in clinical research to characterise brain networks involved in e.g. epileptic activity, or different sensory, motor, and cognitive functions. Yet, preclinical applications are lagging due to technical challenges associated with electrophysiological recordings in the MRI scanner. In recent years, most of the challenges related to data acquisition and analysis have been addressed. This is important because the increasing incidence of neuropsychiatric disorders requires increasingly sophisticated tools for the dissection of their neurobiological mechanisms.
No UK research group has yet combined those methodologies to probe neural circuitry. We propose to set up a multimodal electrophysiology platform, which could be used for both stand-alone experiments and combined with fMRI, behavioural assays, sensory and optogenetic stimulations. By allowing us to make all these recordings simultaneously within the same animal (thus also reducing the use of animals) and over long periods of time (i.e. longitudinally), this approach will allow for much-needed exploration of fundamental neurophysiological processes (e.g. sleep, cognition, auditory processing) across the lifespan and in brain disorders. Our proposal has the potential to positively impact future healthcare in the UK. For example, our proposed studies of the auditory system could benefit future approaches to treat debilitating age-related hearing loss which, in the UK, affects 42% of people over 50 years of age and 71% of those over 70. Similarly, autism affects 1 in 57 children in the UK, costing society >£32 billion/year, and there are still no effective treatments due to our poor understanding of causal neurobiological mechanisms. The proposed equipment and the experimental approach will allow us to develop better understanding of the neural basis of behaviour, including brain function and dysfunction. Given the IoPPN's world-leading portfolio of clinical neuropsychiatric research, especially using MRI and electrophysiological methods, this preclinical capability would provide a much-needed translational link between animal models and human disorders.
Such an approach has proven valuable in elucidating the neural basis of the blood oxygenation level dependant (BOLD) fMRI signal. The combination of electroencephalography (EEG) and fMRI is increasingly used in clinical research to characterise brain networks involved in e.g. epileptic activity, or different sensory, motor, and cognitive functions. Yet, preclinical applications are lagging due to technical challenges associated with electrophysiological recordings in the MRI scanner. In recent years, most of the challenges related to data acquisition and analysis have been addressed. This is important because the increasing incidence of neuropsychiatric disorders requires increasingly sophisticated tools for the dissection of their neurobiological mechanisms.
No UK research group has yet combined those methodologies to probe neural circuitry. We propose to set up a multimodal electrophysiology platform, which could be used for both stand-alone experiments and combined with fMRI, behavioural assays, sensory and optogenetic stimulations. By allowing us to make all these recordings simultaneously within the same animal (thus also reducing the use of animals) and over long periods of time (i.e. longitudinally), this approach will allow for much-needed exploration of fundamental neurophysiological processes (e.g. sleep, cognition, auditory processing) across the lifespan and in brain disorders. Our proposal has the potential to positively impact future healthcare in the UK. For example, our proposed studies of the auditory system could benefit future approaches to treat debilitating age-related hearing loss which, in the UK, affects 42% of people over 50 years of age and 71% of those over 70. Similarly, autism affects 1 in 57 children in the UK, costing society >£32 billion/year, and there are still no effective treatments due to our poor understanding of causal neurobiological mechanisms. The proposed equipment and the experimental approach will allow us to develop better understanding of the neural basis of behaviour, including brain function and dysfunction. Given the IoPPN's world-leading portfolio of clinical neuropsychiatric research, especially using MRI and electrophysiological methods, this preclinical capability would provide a much-needed translational link between animal models and human disorders.
Technical Summary
One of the major goals of neuroscience - to understand how brain function emerges through the interaction of specific neuronal circuits - is hampered by a lack of specific and direct methods to study such processes. However, the development of such methodologies is urgently needed due to the increasing incidence of neurodevelopmental and neurodegenerative disorders, for most of which we still do not know the underlying mechanisms, and do not have disease biomarkers or effective treatments.
To address this key methodological gap, we propose simultaneous recordings of electrophysiological and fMRI measurements in mice and rats. By capitalizing on the strengths of these two methodologies (while compensating for their weaknesses), this "hybrid" approach can provide information necessary for understanding temporal and spatial aspects of information processing in neural circuits, both of which are necessary for the understanding of brain function in health and disease. Furthermore, during such simultaneous recordings, the same neural activity (e.g. as a consequence of sensory or optogenetic stimulation) contributes to the electrophysiology and fMRI data thus providing causal, and not just correlational information.
Such multimodal measurements performed simultaneously within the same animal, provide richer, better-quality data, while at the same time reducing the number of animals used. Moreover, this cutting-edge methodology also allows for these measurements to be recorded longitudinally, which will enable much-needed exploration of fundamental neurophysiological processes, e.g. sleep, memory, and sensory processing, across the lifecourse and in brain disorders.
Because the proposed methodology is increasingly also used in clinical research (e.g. EEG coupled with fMRI), including at the IoPPN, the development of this preclinical capability will strongly contribute to our translational efforts by bridging the gap between animal models and human disorders.
To address this key methodological gap, we propose simultaneous recordings of electrophysiological and fMRI measurements in mice and rats. By capitalizing on the strengths of these two methodologies (while compensating for their weaknesses), this "hybrid" approach can provide information necessary for understanding temporal and spatial aspects of information processing in neural circuits, both of which are necessary for the understanding of brain function in health and disease. Furthermore, during such simultaneous recordings, the same neural activity (e.g. as a consequence of sensory or optogenetic stimulation) contributes to the electrophysiology and fMRI data thus providing causal, and not just correlational information.
Such multimodal measurements performed simultaneously within the same animal, provide richer, better-quality data, while at the same time reducing the number of animals used. Moreover, this cutting-edge methodology also allows for these measurements to be recorded longitudinally, which will enable much-needed exploration of fundamental neurophysiological processes, e.g. sleep, memory, and sensory processing, across the lifecourse and in brain disorders.
Because the proposed methodology is increasingly also used in clinical research (e.g. EEG coupled with fMRI), including at the IoPPN, the development of this preclinical capability will strongly contribute to our translational efforts by bridging the gap between animal models and human disorders.
