Peter J. Hellyer

The entropic brain: a theory of conscious states informed by neuroimaging research with psychedelic drugs

Entropy is a dimensionless quantity that is used for measuring uncertainty about the state of a system but it can also imply physical qualities, where high entropy is synonymous with high disorder. Entropy is applied here in the context of states of consciousness and their associated neurodynamics, with a particular focus on the psychedelic state. The psychedelic state is considered an exemplar of a primitive or primary state of consciousness that preceded the development of modern, adult, human, normal waking consciousness. Based on neuroimaging data with psilocybin, a classic psychedelic drug, it is argued that the defining feature of “primary states” is elevated entropy in certain aspects of brain function, such as the repertoire of functional connectivity motifs that form and fragment across time. Indeed, since there is a greater repertoire of connectivity motifs in the psychedelic state than in normal waking consciousness, this implies that primary states may exhibit “criticality,” i.e., the property of being poised at a “critical” point in a transition zone between order and disorder where certain phenomena such as power-law scaling appear. Moreover, if primary states are critical, then this suggests that entropy is suppressed in normal waking consciousness, meaning that the brain operates just below criticality. It is argued that this entropy suppression furnishes normal waking consciousness with a constrained quality and associated metacognitive functions, including reality-testing and self-awareness. It is also proposed that entry into primary states depends on a collapse of the normally highly organized activity within the default-mode network (DMN) and a decoupling between the DMN and the medial temporal lobes (which are normally significantly coupled). These hypotheses can be tested by examining brain activity and associated cognition in other candidate primary states such as rapid eye movement (REM) sleep and early psychosis and comparing these with non-primary states such as normal waking consciousness and the anaesthetized state.

Neural correlates of the LSD experience revealed by multimodal neuroimaging

Significance Lysergic acid diethylamide (LSD), the prototypical “psychedelic,” may be unique among psychoactive substances. In the decades that followed its discovery, the magnitude of its effect on science, the arts, and society was unprecedented. LSD produces profound, sometimes life-changing experiences in microgram doses, making it a particularly powerful scientific tool. Here we sought to examine its effects on brain activity, using cutting-edge and complementary neuroimaging techniques in the first modern neuroimaging study of LSD. Results revealed marked changes in brain blood flow, electrical activity, and network communication patterns that correlated strongly with the drug’s hallucinatory and other consciousness-altering properties. These results have implications for the neurobiology of consciousness and for potential applications of LSD in psychological research. Lysergic acid diethylamide (LSD) is the prototypical psychedelic drug, but its effects on the human brain have never been studied before with modern neuroimaging. Here, three complementary neuroimaging techniques: arterial spin labeling (ASL), blood oxygen level-dependent (BOLD) measures, and magnetoencephalography (MEG), implemented during resting state conditions, revealed marked changes in brain activity after LSD that correlated strongly with its characteristic psychological effects. Increased visual cortex cerebral blood flow (CBF), decreased visual cortex alpha power, and a greatly expanded primary visual cortex (V1) functional connectivity profile correlated strongly with ratings of visual hallucinations, implying that intrinsic brain activity exerts greater influence on visual processing in the psychedelic state, thereby defining its hallucinatory quality. LSD’s marked effects on the visual cortex did not significantly correlate with the drug’s other characteristic effects on consciousness, however. Rather, decreased connectivity between the parahippocampus and retrosplenial cortex (RSC) correlated strongly with ratings of “ego-dissolution” and “altered meaning,” implying the importance of this particular circuit for the maintenance of “self” or “ego” and its processing of “meaning.” Strong relationships were also found between the different imaging metrics, enabling firmer inferences to be made about their functional significance. This uniquely comprehensive examination of the LSD state represents an important advance in scientific research with psychedelic drugs at a time of growing interest in their scientific and therapeutic value. The present results contribute important new insights into the characteristic hallucinatory and consciousness-altering properties of psychedelics that inform on how they can model certain pathological states and potentially treat others.

The Control of Global Brain Dynamics: Opposing Actions of Frontoparietal Control and Default Mode Networks on Attention

Understanding how dynamic changes in brain activity control behavior is a major challenge of cognitive neuroscience. Here, we consider the brain as a complex dynamic system and define two measures of brain dynamics: the synchrony of brain activity, measured by the spatial coherence of the BOLD signal across regions of the brain; and metastability, which we define as the extent to which synchrony varies over time. We investigate the relationship among brain network activity, metastability, and cognitive state in humans, testing the hypothesis that global metastability is “tuned” by network interactions. We study the following two conditions: (1) an attentionally demanding choice reaction time task (CRT); and (2) an unconstrained “rest” state. Functional MRI demonstrated increased synchrony, and decreased metastability was associated with increased activity within the frontoparietal control/dorsal attention network (FPCN/DAN) activity and decreased default mode network (DMN) activity during the CRT compared with rest. Using a computational model of neural dynamics that is constrained by white matter structure to test whether simulated changes in FPCN/DAN and DMN activity produce similar effects, we demonstate that activation of the FPCN/DAN increases global synchrony and decreases metastability. DMN activation had the opposite effects. These results suggest that the balance of activity in the FPCN/DAN and DMN might control global metastability, providing a mechanistic explanation of how attentional state is shifted between an unfocused/exploratory mode characterized by high metastability, and a focused/constrained mode characterized by low metastability.

Homological scaffolds of brain functional networks

Networks, as efficient representations of complex systems, have appealed to scientists for a long time and now permeate many areas of science, including neuroimaging (Bullmore and Sporns 2009 Nat. Rev. Neurosci. 10, 186–198. (doi:10.1038/nrn2618)). Traditionally, the structure of complex networks has been studied through their statistical properties and metrics concerned with node and link properties, e.g. degree-distribution, node centrality and modularity. Here, we study the characteristics of functional brain networks at the mesoscopic level from a novel perspective that highlights the role of inhomogeneities in the fabric of functional connections. This can be done by focusing on the features of a set of topological objects—homological cycles—associated with the weighted functional network. We leverage the detected topological information to define the homological scaffolds, a new set of objects designed to represent compactly the homological features of the correlation network and simultaneously make their homological properties amenable to networks theoretical methods. As a proof of principle, we apply these tools to compare resting-state functional brain activity in 15 healthy volunteers after intravenous infusion of placebo and psilocybin—the main psychoactive component of magic mushrooms. The results show that the homological structure of the brains functional patterns undergoes a dramatic change post-psilocybin, characterized by the appearance of many transient structures of low stability and of a small number of persistent ones that are not observed in the case of placebo.

Estimating time-varying brain connectivity networks from functional MRI time series

At the forefront of neuroimaging is the understanding of the functional architecture of the human brain. In most applications functional networks are assumed to be stationary, resulting in a single network estimated for the entire time course. However recent results suggest that the connectivity between brain regions is highly non-stationary even at rest. As a result, there is a need for new brain imaging methodologies that comprehensively account for the dynamic nature of functional networks. In this work we propose the Smooth Incremental Graphical Lasso Estimation (SINGLE) algorithm which estimates dynamic brain networks from fMRI data. We apply the proposed algorithm to functional MRI data from 24 healthy patients performing a Choice Reaction Task to demonstrate the dynamic changes in network structure that accompany a simple but attentionally demanding cognitive task. Using graph theoretic measures we show that the properties of the Right Inferior Frontal Gyrus and the Right Inferior Parietal lobe dynamically change with the task. These regions are frequently reported as playing an important role in cognitive control. Our results suggest that both these regions play a key role in the attention and executive function during cognitively demanding tasks and may be fundamental in regulating the balance between other brain regions.

Disconnection of network hubs and cognitive impairment after traumatic brain injury.

Traumatic brain injury (TBI) affects brain connectivity, which disrupts the large-scale networks that support cognitive function. Fagerholm et al. use graph analysis, with brain regions as nodes and white matter tracts as connections, to show that TBI particularly disrupts the connectivity of hubs, and that this disconnection predicts cognitive impairment.

Individual prediction of white matter injury following traumatic brain injury

Traumatic brain injury (TBI) often results in traumatic axonal injury (TAI). This can be difficult to identify using conventional imaging. Diffusion tensor imaging (DTI) offers a method of assessing axonal damage in vivo, but has previously mainly been used to investigate groups of patients. Machine learning techniques are increasingly used to improve diagnosis based on complex imaging measures. We investigated whether machine learning applied to DTI data can be used to diagnose white matter damage after TBI and to predict neuropsychological outcome in individual patients.

Amyloid pathology and axonal injury after brain trauma

Objective: To image β-amyloid (Aβ) plaque burden in long-term survivors of traumatic brain injury (TBI), test whether traumatic axonal injury and Aβ are correlated, and compare the spatial distribution of Aβ to Alzheimer disease (AD). Methods: Patients 11 months to 17 years after moderate–severe TBI underwent 11C-Pittsburgh compound B (11C-PiB)-PET, structural and diffusion MRI, and neuropsychological examination. Healthy aged controls and patients with AD underwent PET and structural MRI. Binding potential (BPND) images of 11C-PiB, which index Aβ plaque density, were computed using an automatic reference region extraction procedure. Voxelwise and regional differences in BPND were assessed. In TBI, a measure of white matter integrity, fractional anisotropy, was estimated and correlated with 11C-PiB BPND. Results: Twenty-eight participants (9 with TBI, 9 controls, 10 with AD) were assessed. Increased 11C-PiB BPND was found in TBI vs controls in the posterior cingulate cortex and cerebellum. Binding in the posterior cingulate cortex increased with decreasing fractional anisotropy of associated white matter tracts and increased with time since injury. Compared to AD, binding after TBI was lower in neocortical regions but increased in the cerebellum. Conclusions: Increased Aβ burden was observed in TBI. The distribution overlaps with, but is distinct from, that of AD. This suggests a mechanistic link between TBI and the development of neuropathologic features of dementia, which may relate to axonal damage produced by the injury.

Cognitive Flexibility through Metastable Neural Dynamics Is Disrupted by Damage to the Structural Connectome

Current theory proposes that healthy neural dynamics operate in a metastable regime, where brain regions interact to simultaneously maximize integration and segregation. Metastability may confer important behavioral properties, such as cognitive flexibility. It is increasingly recognized that neural dynamics are constrained by the underlying structural connections between brain regions. An important challenge is, therefore, to relate structural connectivity, neural dynamics, and behavior. Traumatic brain injury (TBI) is a pre-eminent structural disconnection disorder whereby traumatic axonal injury damages large-scale connectivity, producing characteristic cognitive impairments, including slowed information processing speed and reduced cognitive flexibility, that may be a result of disrupted metastable dynamics. Therefore, TBI provides an experimental and theoretical model to examine how metastable dynamics relate to structural connectivity and cognition. Here, we use complementary empirical and computational approaches to investigate how metastability arises from the healthy structural connectome and relates to cognitive performance. We found reduced metastability in large-scale neural dynamics after TBI, measured with resting-state functional MRI. This reduction in metastability was associated with damage to the connectome, measured using diffusion MRI. Furthermore, decreased metastability was associated with reduced cognitive flexibility and information processing. A computational model, defined by empirically derived connectivity data, demonstrates how behaviorally relevant changes in neural dynamics result from structural disconnection. Our findings suggest how metastable dynamics are important for normal brain function and contingent on the structure of the human connectome.

Effects of lesions on synchrony and metastability in cortical networks

At the macroscopic scale, the human brain can be described as a complex network of white matter tracts integrating grey matter assemblies - the human connectome. The structure of the connectome, which is often described using graph theoretic approaches, can be used to model macroscopic brain function at low computational cost. Here, we use the Kuramoto model of coupled oscillators with time-delays, calibrated with respect to empirical functional MRI data, to study the relation between the structure of the connectome and two aspects of functional brain dynamics - synchrony, a measure of general coherence, and metastability, a measure of dynamical flexibility. Specifically, we investigate the relationship between the local structure of the connectome, quantified using graph theory, and the synchrony and metastability of the models dynamics. By removing individual nodes and all of their connections from the model, we study the effect of lesions on both global and local dynamics. Of the nine nodal graph-theoretical properties tested, two were able to predict effects of node lesion on the global dynamics. The removal of nodes with high eigenvector centrality leads to decreases in global synchrony and increases in global metastability, as does the removal of hub nodes joining topologically segregated network modules. At the level of local dynamics in the neighbourhood of the lesioned node, structural properties of the lesioned nodes hold more predictive power, as five nodal graph theoretical measures are related to changes in local dynamics following node lesions. We discuss these results in the context of empirical studies of stroke and functional brain dynamics.