Publications

Losing Control Under Ketamine: Suppressed Cortico-Hippocampal Drive Following Acute Ketamine in Rats

The Cumulative Effects of Predictability on Synaptic Gain in the Auditory Processing Stream

Stimulus predictability can lead to substantial modulations of brain activity, such as shifts in sustained magnetic field amplitude, measured with magnetoencephalography (MEG). Here, we provide a mechanistic explanation of these effects using MEG data acquired from healthy human volunteers (<i>N</i> = 13, 7 female). In a source-level analysis of induced responses, we established the effects of orthogonal predictability manipulations of rapid tone-pip sequences (namely, sequence regularity and alphabet size) along the auditory processing stream. In auditory cortex, regular sequences with smaller alphabets induced greater gamma activity. Furthermore, sequence regularity shifted induced activity in frontal regions toward higher frequencies. To model these effects in terms of the underlying neurophysiology, we used dynamic causal modeling for cross-spectral density and estimated slow fluctuations in neural (postsynaptic) gain. Using the model-based parameters, we accurately explain the sensor-level sustained field amplitude, demonstrating that slow changes in synaptic efficacy, combined with sustained sensory input, can result in profound and sustained effects on neural responses to predictable sensory streams. <b>SIGNIFICANCE STATEMENT</b> Brain activity can be strongly modulated by the predictability of stimuli it is currently processing. An example of such a modulation is a shift in sustained magnetic field amplitude, measured with magnetoencephalography. Here, we provide a mechanistic explanation of these effects. First, we establish the oscillatory neural correlates of independent predictability manipulations in hierarchically distinct areas of the auditory processing stream. Next, we use a biophysically realistic computational model to explain these effects in terms of the underlying neurophysiology. Finally, using the model-based parameters describing neural gain modulation, we can explain the previously unexplained effects observed at the sensor level. This demonstrates that slow modulations of synaptic gain can result in profound and sustained effects on neural activity.

Dynamic causal modelling of anticipatory skin conductance responses

Anticipatory skin conductance responses [SCRs] are a widely used measure of aversive conditioning in humans. Here, we describe a dynamic causal model [DCM] of how anticipatory, evoked, and spontaneous skin conductance changes are generated by sudomotor nerve activity. Inversion of this model, using variational Bayes, provides a means of inferring the most likely sympathetic nerve activity, given observed skin conductance responses. In two fear conditioning experiments, we demonstrate the predictive validity of the DCM by showing it has greater sensitivity to the effects of conditioning, relative to alternative (conventional) response estimates. Furthermore, we establish face validity by showing that trial-by-trial estimates of anticipatory sudomotor activity are better predicted by formal learning models, relative to response estimates from peak-scoring approaches. The model furnishes a potentially powerful approach to characterising SCR that exploits knowledge about how these signals are generated.

A beautiful loop: An active inference theory of consciousness

Can active inference model consciousness? We offer three conditions implying that it can. The first condition is the simulation of a reality or generative world model, which determines what can be known or acted upon; namely an epistemic field. The second is inferential competition to enter the world model. Only the inferences that coherently reduce long-term uncertainty win, evincing a selection for consciousness that we call Bayesian binding. The third is epistemic depth, which is the recurrent sharing of the Bayesian beliefs throughout the system. Due to this recursive loop — in a hierarchical system (such as a brain) — the world model contains the knowledge that it exists. This is distinct from self-consciousness, because the world model knows itself non-locally and continuously evidences this knowing (i.e., field-evidencing). Formally, we propose a hyper-model for precision-control across the entire hierarchy, whose latent states (or parameters) encode and control the overall structure and weighting rules for all layers of inference. This Beautiful Loop Theory is deeply revealing about meditation, psychedelic, and altered states, minimal phenomenal experience, and provides a new vision for conscious artificial intelligence.

Mixtures of general linear models for functional neuroimaging

We set out a new general framework for making inferences from neuroimaging data, which includes a standard approach to neuroimaging analysis, statistical parametric mapping (SPM), as a special case. The model offers numerous conceptual and statistical advantages that derive from analyzing data at the "cluster level" rather than the "voxel level" and from explicit modeling of the shape and position of clusters of activation. This provides a natural and principled way to pool data from nearby voxels for parameter and variance-component estimation. The model can also be viewed as performing a spatio-temporal cluster analysis. The parameters of the model are estimated using an expectation maximization (EM) algorithm.

Linking structural and effective brain connectivity: structurally informed Parametric Empirical Bayes (si-PEB)

Despite the potential for better understanding functional neuroanatomy, the complex relationship between neuroimaging measures of brain structure and function has confounded integrative, multimodal analyses of brain connectivity. This is particularly true for task-related effective connectivity, which describes the causal influences between neuronal populations. Here, we assess whether measures of structural connectivity may usefully inform estimates of effective connectivity in larger scale brain networks. To this end, we introduce an integrative approach, capitalising on two recent statistical advances: Parametric Empirical Bayes, which provides group-level estimates of effective connectivity, and Bayesian model reduction, which enables rapid comparison of competing models. Crucially, we show that structural priors derived from high angular resolution diffusion imaging on a dynamic causal model of a 12-region network—based on functional MRI data from the same subjects—substantially improve model evidence (posterior probability 1.00). This provides definitive evidence that structural and effective connectivity depend upon each other in mediating distributed, large-scale interactions in the brain. Furthermore, this work offers novel perspectives for understanding normal brain architecture and its disintegration in clinical conditions.

Nonlinear spatial normalization using basis functions

We describe a comprehensive framework for performing rapid and automatic nonlabel-based nonlinear spatial normalizations. The approach adopted minimizes the residual squared difference between an image and a template of the same modality. In order to reduce the number of parameters to be fitted, the nonlinear warps are described by a linear combination of low spatial frequency basis functions. The objective is to determine the optimum coefficients for each of the bases by minimizing the sum of squared differences between the image and template, while simultaneously maximizing the smoothness of the transformation using a maximum a posteriori (MAP) approach. Most MAP approaches assume that the variance associated with each voxel is already known and that there is no covariance between neighboring voxels. The approach described here attempts to estimate this variance from the data, and also corrects for the correlations between neighboring voxels. This makes the same approach suitable for the spatial normalization of both high-quality magnetic resonance images, and low-resolution noisy positron emission tomography images. A fast algorithm has been developed that utilizes Taylor's theorem and the separable nature of the basis functions, meaning that most of the nonlinear spatial variability between images can be automatically corrected within a few minutes. Hum. Brain Mapping 7:254–266, 1999. © 1999 Wiley-Liss, Inc.

Correction: Sequential inference as a mode ofcognition and its correlates in fronto-parietaland hippocampal brain regions

Referee report. For: Breeding novel solutions in the brain: a model of Darwinian neurodynamics [version 1; referees: 1 approved]

Neuroanatomical correlates of externally and internally generated human emotion

Objective: Positron emission tomography was used to investigate the neural substrates of normal human emotion and their dependence on the type of emotional stimulus.Method: Twelve healthy female subjects underwent 12 measurements of regional brain activity following the intravenous bolus administration of [ 15 O]H 2 O as they alternated between emotion-generating and control film and recall tasks.Automated image analysis techniques were used to characterize and compare the increases in regional brain activity associated with the emotional response to complex visual (film) and cognitive (recall) stimuli.Results: Film-and recall-generated emotion were each associated with significantly increased activity in the vicinity of the medial prefrontal cortex and thalamus, suggesting that these regions participate in aspects of emotion that do not depend on the nature of the emotional stimulus.Film-generated emotion was associated with significantly greater increases in activity bilaterally in the occipitotemporoparietal cortex, lateral cerebellum, hypothalamus, and a region that includes the anterior temporal cortex, amygdala, and hippocampal formation, suggesting that these regions participate in the emotional response to certain exteroceptive sensory stimuli.Recall-generated sadness was associated with significantly greater increases in activity in the vicinity of the anterior insular cortex, suggesting that this region participates in the emotional response to potentially distressing cognitive or interoceptive sensory stimuli.Conclusions: While this study should be considered preliminary, it identified brain regions that participate in externally and internally generated human emotion.

Recognition of Sequences of Sequences Using Nonlinear Dynamical Systems

Lateral geniculate activations can be detected using intersubject averaging and fMRI

Abstract Applications of fMRI in functional brain imaging are mainly confined to single subject designs, prohibiting the assessment of subject or group by condition interactions (i.e., differential activations) or areas of conjoint activation. In this paper a framework for fMRI group designs, using statistical parametric mapping, is introduced. It is generally believed that intersubject averaging, which requires spatial normalization and smoothing, will decrease the effective spatial resolution of fMRI or its sensitivity. A subcortical activation of the lateral geniculate nucleus (LGN) was therefore chosen to demonstrate the feasibility and power of intersubject averaging in the context of fMRI. Seven volunteers were studied, while looking at a blank screen or radially moving dots. LGN activation was demonstrated in all single subject analyses and in the group analysis.

Metastable Oscillatory Modes emerge from synchronization in the Brain Spacetime Connectome

Abstract A rich repertoire of oscillatory signals is detected from human brains with electro- and magnetoencephalography (EEG/MEG). However, the principles underwriting coherent oscillations and their link with neural activity remain under debate. Here, we revisit the mechanistic hypothesis that transient brain rhythms are a signature of metastable synchronization, occurring at reduced collective frequencies due to delays between brain areas. We consider a system of damped oscillators in the presence of background noise – approximating the short-lived gamma-frequency oscillations generated within neuronal circuits – coupled according to the diffusion weighted tractography between brain areas. Varying the global coupling strength and conduction speed, we identify a critical regime where spatially and spectrally resolved metastable oscillatory modes (MOMs) emerge at sub-gamma frequencies, approximating the MEG power spectra from 89 healthy individuals at rest. Further, we demonstrate that the frequency, duration, and scale of MOMs – as well as the frequency-specific envelope functional connectivity – can be controlled by global parameters, while the connectome structure remains unchanged. Grounded in the physics of delay-coupled oscillators, these numerical analyses demonstrate how interactions between locally generated fast oscillations in the connectome spacetime structure can lead to the emergence of collective brain rhythms organized in space and time.

Advanced Neuroscience Technologies

Measurement of the Mapping between Intracranial EEG and fMRI Recordings in the Human Brain

There are considerable gaps in our understanding of the relationship between human brain activity measured at different temporal and spatial scales. Here, electrocorticography (ECoG) measures were used to predict functional MRI changes in the sensorimotor cortex in two brain states: at rest and during motor performance. The specificity of this relationship to spatial co-localisation of the two signals was also investigated. We acquired simultaneous ECoG-fMRI in the sensorimotor cortex of three patients with epilepsy. During motor activity, high gamma power was the only frequency band where the electrophysiological response was co-localised with fMRI measures across all subjects. The best model of fMRI changes across states was its principal components, a parsimonious description of the entire ECoG spectrogram. This model performed much better than any others that were based either on the classical frequency bands or on summary measures of cross-spectral changes. The region-specific fMRI signal is reflected in spatially and spectrally distributed EEG activity.

White matter disruption as a cause or consequence of schizophrenia: A Mendelian randomization study

Brief abstract Schizophrenia is hypothesized to be caused by impaired functional integration in the brain, and this could hypothetically be caused by white matter disruptions, synaptic dysfunction, or both. Neuroimaging studies consistently show reduced fractional anisotropy, a measure of white matter integrity, in patients with schizophrenia. Using Mendelian randomization, we show that these white matter changes are likely to be the consequence of a primary synaptopathy in schizophrenia.

<i>In vitro</i> neurons learn and exhibit sentience when embodied in a simulated game-world

Integrating neurons into digital systems to leverage their innate intelligence may enable performance infeasible with silicon alone, along with providing insight into the cellular origin of intelligence. We developed DishBrain , a system which exhibits natural intelligence by harnessing the inherent adaptive computation of neurons in a structured environment. In vitro neural networks from human or rodent origins, are integrated with in silico computing via high-density multielectrode array. Through electrophysiological stimulation and recording, cultures were embedded in a simulated game-world, mimicking the arcade game ‘Pong’. Applying a previously untestable theory of active inference via the Free Energy Principle, we found that learning was apparent within five minutes of real-time gameplay, not observed in control conditions. Further experiments demonstrate the importance of closed-loop structured feedback in eliciting learning over time. Cultures display the ability to self-organise in a goal-directed manner in response to sparse sensory information about the consequences of their actions.

Resilience and Active Inference

In this paper, we aim to conceptualize and formalize the construct of resilience using the tools of active inference, a new physics-based modeling approach apt for the description and analysis of complex adaptive systems. We intend this as a first step towards a computational model of resilient systems. We begin by offering a conceptual analysis of resilience, to clarify its meaning, as established in the literature. We examine an orthogonal, threefold distinction between meanings of the word “resilience”: (i) inertia, or the ability to resist change (ii) elasticity, or the ability to bounce back from a perturbation, and (iii) plasticity, or the ability to flexibly expand the repertoire of adaptive states. We then situate all three senses of resilience within active inference. We map resilience as inertia onto high precision beliefs, resilience as elasticity onto relaxation back to characteristic (i.e., attracting) states, and resilience as plasticity onto functional redundancy and structural degeneracy.