Genetic basis of anatomical asymmetry and aberrant dynamic functional networks in Alzheimer’s disease

Acknowledgements V.V. conceptualized the study, analysed genetic and fMRI data, drafted the manuscript and supervised the project. N.R. conducted analysis of functional MRI data. V.V and G.R. reviewed the manuscript. V.V. would like to thank Dr Juliane Mueller, Cambridge Clinical Neuroscience, for useful and very informative discussions about gene expressions in healthy and diseased brains. Funding This work is supported by funds from Roland Sutton Academic Trust (RG:#RG13688 and #DSR1058-100).Peer reviewe

The psychological correlates of distinct neural states occurring during wakeful rest

When unoccupied by an explicit external task, humans engage in a wide range of different types of self-generated thinking. These are often unrelated to the immediate environment and have unique psychological features. Although contemporary perspectives on ongoing thought recognise the heterogeneity of these self-generated states, we lack both a clear understanding of how to classify the specific states, and how they can be mapped empirically. In the current study, we capitalise on advances in machine learning that allow continuous neural data to be divided into a set of distinct temporally re-occurring patterns, or states. We applied this technique to a large set of resting state data in which we also acquired retrospective descriptions of the participants' experiences during the scan. We found that two of the identified states were predictive of patterns of thinking at rest. One state highlighted a pattern of neural activity commonly seen during demanding tasks, and the time individuals spent in this state was associated with descriptions of experience focused on problem solving in the future. A second state was associated with patterns of activity that are commonly seen under less demanding conditions, and the time spent in it was linked to reports of intrusive thoughts about the past. Finally, we found that these two neural states tended to fall at either end of a neural hierarchy that is thought to reflect the brain's response to cognitive demands. Together, these results demonstrate that approaches which take advantage of time-varying changes in neural function can play an important role in understanding the repertoire of self-generated states. Moreover, they establish that important features of self-generated ongoing experience are related to variation along a similar vein to those seen when the brain responds to cognitive task demands

Post-stroke upper limb recovery is correlated with dynamic resting-state network connectivity

Motor recovery is still limited for people with stroke especially those with greater functional impairments. In order to improve outcome, we need to understand more about the mechanisms underpinning recovery. Task-unbiased, blood flow–independent post-stroke neural activity can be acquired from resting brain electrophysiological recordings and offers substantial promise to investigate physiological mechanisms, but behaviourally relevant features of resting-state sensorimotor network dynamics have not yet been identified. Thirty-seven people with subcortical ischaemic stroke and unilateral hand paresis of any degree were longitudinally evaluated at 3 weeks (early subacute) and 12 weeks (late subacute) after stroke. Resting-state magnetoencephalography and clinical scores of motor function were recorded and compared with matched controls. Magnetoencephalography data were decomposed using a data-driven hidden Markov model into 10 time-varying resting-state networks. People with stroke showed statistically significantly improved Action Research Arm Test and Fugl-Meyer upper extremity scores between 3 weeks and 12 weeks after stroke (both P < 0.001). Hidden Markov model analysis revealed a primarily alpha-band ipsilesional resting-state sensorimotor network which had a significantly increased life-time (the average time elapsed between entering and exiting the network) and fractional occupancy (the occupied percentage among all networks) at 3 weeks after stroke when compared with controls. The life-time of the ipsilesional resting-state sensorimotor network positively correlated with concurrent motor scores in people with stroke who had not fully recovered. Specifically, this relationship was observed only in ipsilesional rather in contralesional sensorimotor network, default mode network or visual network. The ipsilesional sensorimotor network metrics were not significantly different from controls at 12 weeks after stroke. The increased recruitment of alpha-band ipsilesional resting-state sensorimotor network at subacute stroke served as functionally correlated biomarkers exclusively in people with stroke with not fully recovered hand paresis, plausibly reflecting functional motor recovery processes

The Gaussian-Linear Hidden Markov model: a Python package

We propose the Gaussian-Linear Hidden Markov model (GLHMM), a generalisation of different types of HMMs commonly used in neuroscience. In short, the GLHMM is a general framework where linear regression is used to flexibly parameterise the Gaussian state distribution, thereby accommodating a wide range of uses -including unsupervised, encoding and decoding models. GLHMM is implemented as a Python toolbox with an emphasis on statistical testing and out-of-sample prediction -i.e. aimed at finding and characterising brain-behaviour associations. The toolbox uses a stochastic variational inference approach, enabling it to handle large data sets at reasonable computational time. Overall, the approach can be applied to several data modalities, including animal recordings or non-brain data, and applied over a broad range of experimental paradigms. For demonstration, we show examples with fMRI, electrocorticography, magnetoencephalo-graphy and pupillometry.Comment: 22 pages, 7 figures, 1 tabl

Can biological quantum networks solve NP-hard problems?

There is a widespread view that the human brain is so complex that it cannot be efficiently simulated by universal Turing machines. During the last decades the question has therefore been raised whether we need to consider quantum effects to explain the imagined cognitive power of a conscious mind. This paper presents a personal view of several fields of philosophy and computational neurobiology in an attempt to suggest a realistic picture of how the brain might work as a basis for perception, consciousness and cognition. The purpose is to be able to identify and evaluate instances where quantum effects might play a significant role in cognitive processes. Not surprisingly, the conclusion is that quantum-enhanced cognition and intelligence are very unlikely to be found in biological brains. Quantum effects may certainly influence the functionality of various components and signalling pathways at the molecular level in the brain network, like ion ports, synapses, sensors, and enzymes. This might evidently influence the functionality of some nodes and perhaps even the overall intelligence of the brain network, but hardly give it any dramatically enhanced functionality. So, the conclusion is that biological quantum networks can only approximately solve small instances of NP-hard problems. On the other hand, artificial intelligence and machine learning implemented in complex dynamical systems based on genuine quantum networks can certainly be expected to show enhanced performance and quantum advantage compared with classical networks. Nevertheless, even quantum networks can only be expected to efficiently solve NP-hard problems approximately. In the end it is a question of precision - Nature is approximate.Comment: 38 page

Linking fast and slow: the case for generative models

A pervasive challenge in neuroscience is testing whether neuronal connectivity changes over time due to specific causes, such as stimuli, events, or clinical interventions. Recent hardware innovations and falling data storage costs enable longer, more naturalistic neuronal recordings. The implicit opportunity for understanding the self-organised brain calls for new analysis methods that link temporal scales: from the order of milliseconds over which neuronal dynamics evolve, to the order of minutes, days or even years over which experimental observations unfold. This review article demonstrates how hierarchical generative models and Bayesian inference help to characterise neuronal activity across different time scales. Crucially, these methods go beyond describing statistical associations among observations and enable inference about underlying mechanisms. We offer an overview of fundamental concepts in state-space modeling and suggest a taxonomy for these methods. Additionally, we introduce key mathematical principles that underscore a separation of temporal scales, such as the slaving principle, and review Bayesian methods that are being used to test hypotheses about the brain with multi-scale data. We hope that this review will serve as a useful primer for experimental and computational neuroscientists on the state of the art and current directions of travel in the complex systems modelling literature.Comment: 20 pages, 5 figure

Brain network signatures of depressive symptoms

Depressive symptoms are common in the general population. Even in individuals who do not meet the criteria for a Major Depression Disorder (MDD), their symptoms are of clinical relevance because they increase the likelihood of progressing into a full-blown depressive episode, which in turn increases the prevalence of future episodes. The studies in this thesis apply advanced computational methods to functional magnetic resonance imaging (fMRI) data to investigate the dynamics of network connectivity, with the aim of understanding what brain mechanisms make a person more vulnerable to depression. Our results suggest that imbalances in whole-brain connectivity can already be linked to higher levels of depressive symptoms in healthy (undiagnosed) individuals. These imbalances correspond to a reduced dynamism in the overall functional organization of the brain, suggesting a link between a ‘rigid brain’ and rigid behavior, such as the lack of flexibility in cognitive and emotional responses that often accompanies depressive symptoms. Additionally, individual differences in the repertoire of brain states indicate that people with more depressive symptoms engage more in states related to self-referential thinking. This tendency was also observed in remitted patients during the transition into a depressive episode. This emphasizes that the present experience of depressive symptoms, whether in healthy individuals or MDD patients, is associated with changes in brain communication. The findings of this thesis lead to a deeper understanding of the complex orchestration of brain communication and its changes concerning depressive symptomatology in clinical and nonclinical populations

Post-stroke upper limb recovery is correlated with dynamic resting-state network connectivity

Motor recovery is still limited for people with stroke especially those with greater functional impairments. In order to improve outcome, we need to understand more about the mechanisms underpinning recovery. Task-unbiased, blood-flow independent post-stroke neural activity can be acquired from resting brain electrophysiological recordings, and offers substantial promise to investigate physiological mechanisms, but behaviourally-relevant features of resting-state sensorimotor network dynamics have not yet been identified. Thirty-seven people with subcortical ischemic stroke and unilateral hand paresis of any degree were longitudinally evaluated at 3 weeks (early subacute) and 12 weeks (late subacute) after stroke. Resting-state magnetoencephalography and clinical scores of motor function were recorded and compared with matched controls. Magnetoencephalography data were decomposed using a data-driven Hidden Markov Model into 10 time-varying resting-state networks. People with stroke showed statistically significantly improved Action Research Arm Test and Fugl-Meyer upper extremity scores between 3 weeks and 12 weeks after stroke (both p &lt; 0.001). Hidden Markov Model analysis revealed a primarily alpha-band ipsilesional resting-state sensorimotor network which had a significantly increased life-time (the average time elapsed between entering and exiting the network) and fractional occupancy (the occupied percentage among all networks) at 3 weeks after stroke when compared to controls. The life-time of the ipsilesional resting-state sensorimotor network positively correlated with concurrent motor scores in people with stroke who had not fully recovered. Specifically, this relationship was observed only in ipsilesional rather in contralesional sensorimotor network, default mode network or visual network. The ipsilesional sensorimotor network metrics were not significantly different from controls at 12 weeks after stroke. The increased recruitment of alpha-band ipsilesional resting-state sensorimotor network at subacute stroke served as functionally correlated biomarkers exclusively in people with stroke with not fully recovered hand paresis, plausibly reflecting functional motor recovery processes