Tangling with the Entangled Brain: Putting the Global Back into the Local.

Pessoa's precis "The Entangled Brain" is a call to action. The larger concepts resonate with existing complex systems frameworks in general and in neuroscience in particular, especially in the fields of connectomics and criticality (Cocchi, Gollo, Zalesky, & Breakspear, 2017; Bassett & Gazzaniga, 2011). What is provocative from our perspective is that despite recognizing the brain as a complex system, the experimental approaches adopted by our community largely fail to align with this recognition. In this commentary, we lay out the fundamental challenge Pessoa brings to the neuroscience community: to engage with the brain, conceptually and experimentally, as a complex whole.

Dynamic trajectories of connectome state transitions are heritable.

The brain's functional connectome is dynamic, constantly reconfiguring in an individual-specific manner. However, which characteristics of such reconfigurations are subject to genetic effects, and to what extent, is largely unknown. Here, we identified heritable dynamic features, quantified their heritability, and determined their association with cognitive phenotypes. In resting-state fMRI, we obtained multivariate features, each describing a temporal or spatial characteristic of connectome dynamics jointly over a set of connectome states. We found strong evidence for heritability of temporal features, particularly, Fractional Occupancy (FO) and Transition Probability (TP), representing the duration spent in each connectivity configuration and the frequency of shifting between configurations, respectively. These effects were robust against methodological choices of number of states and global signal regression. Genetic effects explained a substantial proportion of phenotypic variance of these features (h2=0.39, 95% CI= [.24,.54] for FO; h2=0.43, 95% CI=[.29,.57] for TP). Moreover, these temporal phenotypes were associated with cognitive performance. Contrarily, we found no robust evidence for heritability of spatial features of the dynamic states (i.e., states' Modularity and connectivity pattern). Genetic effects may therefore primarily contribute to how the connectome transitions across states, rather than the precise spatial instantiation of the states in individuals. In sum, genetic effects impact the dynamic trajectory of state transitions (captured by FO and TP), and such temporal features may act as endophenotypes for cognitive abilities.

Metastable neural dynamics underlies cognitive performance across multiple behavioural paradigms.

Despite resting state networks being associated with a variety of cognitive abilities, it remains unclear how these local areas act in concert to express particular cognitive operations. Theoretical and empirical accounts indicate that large-scale resting state networks reconcile dual tendencies towards integration and segregation by operating in a metastable regime of their coordination dynamics. Metastability may confer important behavioural qualities by binding distributed local areas into large-scale neurocognitive networks. We tested this hypothesis by analysing fMRI data in a large cohort of healthy individuals (N = 566) and comparing the metastability of the brain's large-scale resting network architecture at rest and during the performance of several tasks. Metastability was estimated using a well-defined collective variable capturing the level of 'phase-locking' between large-scale networks over time. Task-based reasoning was principally characterised by high metastability in cognitive control networks and low metastability in sensory processing areas. Although metastability between resting state networks increased during task performance, cognitive ability was more closely linked to spontaneous activity. High metastability in the intrinsic connectivity of cognitive control networks was linked to novel problem solving or fluid intelligence, but was less important in tasks relying on previous experience or crystallised intelligence. Crucially, subjects with resting architectures similar or 'pre-configured' to a task-general arrangement demonstrated superior cognitive performance. Taken together, our findings support a key linkage between the spontaneous metastability of large-scale networks in the cerebral cortex and cognition.

Metastable neural dynamics in Alzheimer's disease are disrupted by lesions to the structural connectome.

Current theory suggests brain regions interact to reconcile the competing demands of integration and segregation by leveraging metastable dynamics. An emerging consensus recognises the importance of metastability in healthy neural dynamics where the transition between network states over time is dependent upon the structural connectivity between brain regions. In Alzheimer's disease (AD) - the most common form of dementia - these couplings are progressively weakened, metastability of neural dynamics are reduced and cognitive ability is impaired. Accordingly, we use a joint empirical and computational approach to reveal how behaviourally relevant changes in neural metastability are contingent on the structural integrity of the anatomical connectome. We estimate the metastability of fMRI BOLD signal in subjects from across the AD spectrum and in healthy controls and demonstrate the dissociable effects of structural disconnection on synchrony versus metastability. In addition, we reveal the critical role of metastability in general cognition by demonstrating the link between an individuals cognitive performance and their metastable neural dynamic. Finally, using whole-brain computer modelling, we demonstrate how a healthy neural dynamic is conditioned upon the topological integrity of the structural connectome. Overall, the results of our joint computational and empirical analysis suggest an important causal relationship between metastable neural dynamics, cognition, and the structural efficiency of the anatomical connectome.

Disrupted Thalamus White Matter Anatomy and Posterior Default Mode Network Effective Connectivity in Amnestic Mild Cognitive Impairment.

Alzheimer's disease (AD) and its prodromal state amnestic mild cognitive impairment (aMCI) are characterized by widespread abnormalities in inter-areal white matter fiber pathways and parallel disruption of default mode network (DMN) resting state functional and effective connectivity. In healthy subjects, DMN and task positive network interaction are modulated by the thalamus suggesting that abnormal task-based DMN deactivation in aMCI may be a consequence of impaired thalamo-cortical white matter circuitry. Thus, this article uses a multimodal approach to assess white matter integrity between thalamus and DMN components and associated effective connectivity in healthy controls (HCs) relative to aMCI patients. Twenty-six HC and 20 older adults with aMCI underwent structural, functional and diffusion MRI scanning using the high angular resolution diffusion-weighted acquisition protocol. The DMN of each subject was identified using independent component analysis (ICA) and resting state effective connectivity was calculated between thalamus and DMN nodes. White matter integrity changes between thalamus and DMN were investigated with constrained spherical deconvolution (CSD) tractography. Significant structural deficits in thalamic white matter projection fibers to posterior DMN components posterior cingulate cortex (PCC) and lateral inferior parietal lobe (IPL) were identified together with significantly reduced effective connectivity from left thalamus to left IPL. Crucially, impaired thalamo-cortical white matter circuitry correlated with memory performance. Disrupted thalamo-cortical structure was accompanied by significant reductions in IPL and PCC cortico-cortical effective connectivity. No structural deficits were found between DMN nodes. Abnormal posterior DMN activity may be driven by changes in thalamic white matter connectivity; a view supported by the close anatomical and functional association of thalamic nuclei effected by AD pathology and the posterior DMN nodes. We conclude that dysfunctional posterior DMN activity in aMCI is consistent with disrupted cortico-thalamo-cortical processing and thalamic-based dissemination of hippocampal disease agents to cortical hubs.

Dynamical Structures of Hsp70 and Hsp70-Hsp40 Complexes.

Protein misfolding and aggregation are pathological events that place a significant amount of stress on the maintenance of protein homeostasis (proteostasis). For prevention and repair of protein misfolding and aggregation, cells are equipped with robust mechanisms that mainly rely on molecular chaperones. Two classes of molecular chaperones, heat shock protein 70 kDa (Hsp70) and Hsp40, recognize and bind to misfolded proteins, preventing their toxic biomolecular aggregation and enabling refolding or targeted degradation. Here, we review the current state of structural biology of Hsp70 and Hsp40-Hsp70 complexes and examine the link between their structures, dynamics, and functions. We highlight the power of nuclear magnetic resonance spectroscopy to untangle complex relationships behind molecular chaperones and their mechanism(s) of action.