Functional Connectome
functional connectome
A parsimonious description of global functional brain organization in three spatiotemporal patterns
Resting-state functional magnetic resonance imaging (MRI) has yielded seemingly disparate insights into large-scale organization of the human brain. The brain’s large-scale organization can be divided into two broad categories: zero-lag representations of functional connectivity structure and time-lag representations of traveling wave or propagation structure. In this study, we sought to unify observed phenomena across these two categories in the form of three low-frequency spatiotemporal patterns composed of a mixture of standing and traveling wave dynamics. We showed that a range of empirical phenomena, including functional connectivity gradients, the task-positive/task-negative anti-correlation pattern, the global signal, time-lag propagation patterns, the quasiperiodic pattern and the functional connectome network structure, are manifestations of these three spatiotemporal patterns. These patterns account for much of the global spatial structure that underlies functional connectivity analyses and unifies phenomena in resting-state functional MRI previously thought distinct.
The Synaptome Architecture of the Brain: Lifespan, disease, evolution and behavior
The overall aim of my research is to understand how the organisation of the synapse, with particular reference to the postsynaptic proteome (PSP) of excitatory synapses in the brain, informs the fundamental mechanisms of learning, memory and behaviour and how these mechanisms go awry in neurological dysfunction. The PSP indeed bears a remarkable burden of disease, with components being disrupted in disorders (synaptopathies) including schizophrenia, depression, autism and intellectual disability. Our work has been fundamental in revealing and then characterising the unprecedented complexity (>1000 highly conserved proteins) of the PSP in terms of the subsynaptic architecture of postsynaptic proteins such as PSD95 and how these proteins assemble into complexes and supercomplexes in different neurons and regions of the brain. Characterising the PSPs in multiple species, including human and mouse, has revealed differences in key sets of functionally important proteins, correlates with brain imaging and connectome data, and a differential distribution of disease-relevant proteins and pathways. Such studies have also provided important insight into synapse evolution, establishing that vertebrate behavioural complexity is a product of the evolutionary expansion in synapse proteomes that occurred ~500 million years ago. My lab has identified many mutations causing cognitive impairments in mice before they were found to cause human disorders. Our proteomic studies revealed that >130 brain diseases are caused by mutations affecting postsynaptic proteins. We uncovered mechanisms that explain the polygenic basis and age of onset of schizophrenia, with postsynaptic proteins, including PSD95 supercomplexes, carrying much of the polygenic burden. We discovered the “Genetic Lifespan Calendar”, a genomic programme controlling when genes are regulated. We showed that this could explain how schizophrenia susceptibility genes are timed to exert their effects in young adults. The Genes to Cognition programme is the largest genetic study so far undertaken into the synaptic molecular mechanisms underlying behaviour and physiology. We made important conceptual advances that inform how the repertoire of both innate and learned behaviours is built from unique combinations of postsynaptic proteins that either amplify or attenuate the behavioural response. This constitutes a key advance in understanding how the brain decodes information inherent in patterns of nerve impulses, and provides insight into why the PSP has evolved to be so complex, and consequently why the phenotypes of synaptopathies are so diverse. Our most recent work has opened a new phase, and scale, in understanding synapses with the first synaptome maps of the brain. We have developed next-generation methods (SYNMAP) that enable single-synapse resolution molecular mapping across the whole mouse brain and extensive regions of the human brain, revealing the molecular and morphological features of a billion synapses. This has already uncovered unprecedented spatiotemporal synapse diversity organised into an architecture that correlates with the structural and functional connectomes, and shown how mutations that cause cognitive disorders reorganise these synaptome maps; for example, by detecting vulnerable synapse subtypes and synapse loss in Alzheimer’s disease. This innovative synaptome mapping technology has huge potential to help characterise how the brain changes during normal development, including in specific cell types, and with degeneration, facilitating novel pathways to diagnosis and therapy.
The functional connectome across temporal scales
The view of human brain function has drastically shifted over the last decade, owing to the observation that the majority of brain activity is intrinsic rather than driven by external stimuli or cognitive demands. Specifically, all brain regions continuously communicate in spatiotemporally organized patterns that constitute the functional connectome, with consequences for cognition and behavior. In this talk, I will argue that another shift is underway, driven by new insights from synergistic interrogation of the functional connectome using different acquisition methods. The human functional connectome is typically investigated with functional magnetic resonance imaging (fMRI) that relies on the indirect hemodynamic signal, thereby emphasizing very slow connectivity across brain regions. Conversely, more recent methodological advances demonstrate that fast connectivity within the whole-brain connectome can be studied with real-time methods such as electroencephalography (EEG). Our findings show that combining fMRI with scalp or intracranial EEG in humans, especially when recorded concurrently, paints a rich picture of neural communication across the connectome. Specifically, the connectome comprises both fast, oscillation-based connectivity observable with EEG, as well as extremely slow processes best captured by fMRI. While the fast and slow processes share an important degree of spatial organization, these processes unfold in a temporally independent manner. Our observations suggest that fMRI and EEG may be envisaged as capturing distinct aspects of functional connectivity, rather than intermodal measurements of the same phenomenon. Infraslow fluctuation-based and rapid oscillation-based connectivity of various frequency bands constitute multiple dynamic trajectories through a shared state space of discrete connectome configurations. The multitude of flexible trajectories may concurrently enable functional connectivity across multiple independent sets of distributed brain regions.
A transdiagnostic data-driven study of children’s behaviour and the functional connectome
Behavioural difficulties are seen as hallmarks of many neurodevelopmental conditions. Differences in functional brain organisation have been observed in these conditions, but little is known about how they are related to a child’s profile of behavioural difficulties. We investigated whether behavioural difficulties are associated with how the brain is functionally organised in an intentionally heterogeneous and transdiagnostic sample of 957 children aged 5-15. We used consensus community detection to derive data-driven profiles of behavioural difficulties and constructed functional connectomes from a subset of 238 children with resting-state functional Magnetic Resonance Imaging (fMRI) data. We identified three distinct profiles of behaviour that were characterised by principal difficulties with hot executive function, cool executive function, and learning. Global organisation of the functional connectome did not differ between the groups, but multivariate patterns of connectivity at the level of Intrinsic Connectivity Networks (ICNs), nodes, and hubs significantly predicted group membership in held-out data. Fronto-parietal connector hubs were under-connected in all groups relative to a comparison sample, and children with hot vs cool executive function difficulties were distinguished by connectivity in ICNs associated with cognitive control, emotion processing, and social cognition. This demonstrates both general and specific neurodevelopmental risk factors in the functional connectome. (https://www.medrxiv.org/content/10.1101/2021.09.15.21262637v1)
Learning to aggress – Behavioral and circuit mechanisms of aggression reward
Aggression is an ethologically complex behavior with equally complex underlying mechanisms. Here, I present data on one form of aggression, appetitive or rewarding aggression, and the behavioral, cellular and system-level mechanisms guiding this behavior. First, I will present one way in which appetitive aggression is modeled in mice, and extend aggression motivation to the concept of compulsive aggression seeking and relapse. I will then briefly highlight recent advances in computer vision and machine learning for automated scoring of aggressive behavior, the role of specific cell-types in controlling aggression reward, and close with preliminary data on the whole brain aggression reward functional connectome using light sheet fluorescent microscopy (LSFM).
Development of the whole-brain functional connectome explored via graph theory analysis
FENS Forum 2024