Modelling and analysis of cortico-hippocampal interactions and dynamics during sleep and anaesthesia

The standard memory consolidation model assumes that new memories are temporarily stored in the hippocampus and later transferred to the neocortex, during deep sleep, for long-term storage, signifying the importance of studying functional and structural cortico-hippocampal interactions. Our work offers a thorough analysis on such interactions between neocortex and hippocampus, along with a detailed study of their intrinsic dynamics, from two complementary perspectives: statistical data analysis and computational modelling. The first part of this study reviews mathematical tools for assessing directional interactions in multivariate time series. We focus on the notion of Granger Causality and the related measure of generalised Partial Directed Coherence (gPDC) which we then apply, through a custom built numerical package, to electrophysiological data from the medial prefrontal cortex (mPFC) and hippocampus of anaesthetized rats. Our gPDC analysis reveals a clear lateral-to-medial hippocampus connectivity and suggests a reciprocal information flow between mPFC and hippocampus, altered during cortical activity. The second part deals with modelling sleep-related intrinsic rhythmic dynamics of the two areas, and examining their coupling. We first reproduce a computational model of the cortical slow oscillation, a periodic alteration between activated (UP) states and neuronal silence. We then develop a new spiking network model of hippocampal areas CA3 and CA1, reproducing many of their intrinsic dynamics and exhibiting sharp wave-ripple complexes, suggesting a novel mechanism for their generation based on CA1 interneuronal activity and recurrent inhibition. We finally couple the two models to study interactions between the slow oscillation and hippocampal activity. Our simulations propose a dependence of the correlation between UP states and hippocampal spiking on the excitation-to-inhibition ratio induced by the mossy fibre input to CA3 and by a combination of the Schaffer collateral and temporoammonic input to CA1. These inputs are shown to affect reported correlations between UP states and ripples

Bursts of beta oscillations across the brain as a neurophysiological correlate of contextual novelty

The retrosplenial cortex and hippocampus are brain regions which have been shown to be highly involved in contextual memory. In order to discover neurophysiological correlates of contextual memory in these regions, we used in vivo electrophysiology in awake, behaving mice while they explored a series of novel and familiar environments. Additionally, in order to better understand the specific neurophysiological effects of Alzheimer’s disease-associated amyloid pathology on the retrosplenial cortex and hippocampus, we compared network activity between wild-type mice and J20 mice, a transgenic mouse model which develops widespread age-related amyloid pathology and memory impairments. We detected transient bursts of beta oscillations in both the retrosplenial cortex and hippocampus that were synchronous between these regions and upregulated during contextual novelty. Moreover, spiking of neurons in the retrosplenial cortex was significantly increased during beta bursts. In J20 mice, we noted numerous examples of altered network activity, including aberrant beta bursting which is not coupled to neuronal spiking. Through the use of EEG recordings in mice, we demonstrated that beta bursts can be detected across the cortex, and are highly synchronous between different brain regions. Finally, we demonstrated that it is possible to pharmacologically induce beta bursting in the retrosplenial cortex in vitro through the use of carbachol, a muscarinic acetylcholine receptor agonist, providing an assay for better understanding the mechanisms underlying beta bursting. These findings suggest that transient beta bursting across the brain provides brief windows of effective communication between brain regions, which may underlie the formation of cortical representation of contexts, and may be impaired in Alzheimer’s disease

Mecanismos biofísicos y fuentes de los potenciales extracelulares en el hipocampo

Tesis inédita de la Universidad Complutense de Madrid, Facultad de Ciencias Físicas, Departamento de Física Aplicada III (Electricidad y Electrónica), leída el 20-11-2015Depto. de Estructura de la Materia, Física Térmica y ElectrónicaFac. de Ciencias FísicasTRUEunpu

Modelling and analysis of cortico-hippocampal interactions and dynamics during sleep and anaesthesia

The standard memory consolidation model assumes that new memories are temporarily stored in the hippocampus and later transferred to the neocortex, during deep sleep, for long-term storage, signifying the importance of studying functional and structural cortico-hippocampal interactions. Our work offers a thorough analysis on such interactions between neocortex and hippocampus, along with a detailed study of their intrinsic dynamics, from two complementary perspectives: statistical data analysis and computational modelling. The first part of this study reviews mathematical tools for assessing directional interactions in multivariate time series. We focus on the notion of Granger Causality and the related measure of generalised Partial Directed Coherence (gPDC) which we then apply, through a custom built numerical package, to electrophysiological data from the medial prefrontal cortex (mPFC) and hippocampus of anaesthetized rats. Our gPDC analysis reveals a clear lateral-to-medial hippocampus connectivity and suggests a reciprocal information flow between mPFC and hippocampus, altered during cortical activity. The second part deals with modelling sleep-related intrinsic rhythmic dynamics of the two areas, and examining their coupling. We first reproduce a computational model of the cortical slow oscillation, a periodic alteration between activated (UP) states and neuronal silence. We then develop a new spiking network model of hippocampal areas CA3 and CA1, reproducing many of their intrinsic dynamics and exhibiting sharp wave-ripple complexes, suggesting a novel mechanism for their generation based on CA1 interneuronal activity and recurrent inhibition. We finally couple the two models to study interactions between the slow oscillation and hippocampal activity. Our simulations propose a dependence of the correlation between UP states and hippocampal spiking on the excitation-to-inhibition ratio induced by the mossy fibre input to CA3 and by a combination of the Schaffer collateral and temporoammonic input to CA1. These inputs are shown to affect reported correlations between UP states and ripples

Multimodal characterisation of sensorimotor oscillations

The studies in this project have investigated the ongoing neuronal network oscillatory activity found in the sensorimotor cortex using two modalities: magnetoencephalography (MEG) and in vitro slice recordings. The results have established that ongoing sensorimotor oscillations span the mu and beta frequency region both in vitro and in MEG recordings, with distinct frequency profiles for each recorded laminae in vitro, while MI and SI show less difference in humans. In addition, these studies show that connections between MI and SI modulate the ongoing neuronal network activity in these areas. The stimulation studies indicate that specific frequencies of stimulation affect the ongoing activity in the sensorimotor cortex. The continuous theta burst stimulation (cTBS) study demonstrates that cTBS predominantly enhances the power of the local ongoing activity. The stimulation studies in this project show limited comparison between modalities, which is informative of the role of connectivity in these effects. However, independently these studies provide novel information on the mechanisms on sensorimotor oscillatory interaction. The pharmacological studies reveal that GABAergic modulation with zolpidem changes the neuronal oscillatory network activity in both healthy and pathological MI. Zolpidem enhances the power of ongoing oscillatory activity in both sensorimotor laminae and in healthy subjects. In contrast, zolpidem attenuates the “abnormal” beta oscillatory activity in the affected hemisphere in Parkinsonian patients, while restoring the hemispheric beta power ratio and frequency variability and thereby improving motor symptomatology. Finally we show that independent signals from MI laminae can be integrated in silico to resemble the aggregate MEG MI oscillatory signals. This highlights the usefulness of combining these two methods when elucidating neuronal network oscillations in the sensorimotor cortex and any interventions

Fluorescence Imaging of Cortical Calcium Dynamics: A Tool for Visualizing Mouse Brain Functions, Connections, and Networks

Hemodynamic-based markers of cortical activity (e.g. functional magnetic resonance imaging (fMRI) and optical intrinsic signal imaging) are an indirect and relatively slow report of neural activity driven by electrical and metabolic activity through neurovascular coupling, which presents significant limiting factors in deducing underlying brain network dynamics. As application of resting state functional connectivity (FC) measures is extended further into topics such as brain development, aging, and disease, the importance of understanding the fundamental basis for FC will grow. In this dissertation, we extend functional analysis from hemodynamic- to calcium-based imaging. Transgenic mice expressing a fluorescent calcium indicator (GCaMP6) driven by the Thy1 promoter in glutamatergic neurons were imaged transcranially in both anesthetized (using ketaminze/xylazine) and awake states. Sequential LED illumination (λ=470, 530, 590, 625nm) enabled concurrent imaging of both GCaMP6 fluorescence emission (corrected for hemoglobin absorption) and hemodynamics. EEG measurements of the global cortical field potential were also simultaneously acquired. First, we validated the ability of our system to capture GCaMP6 fluorescence emission and hemodynamics by implementing an electrical somatosensory stimulation paradigm. The neural origins of the GCaMP6 fluorescent signal were further confirmed by histology and by comparing the spectral content of imaged GCaMP6 activity to concurrently-acquired EEG. We then constructed seed-based FC and coherence network maps for low (0.009-0.08Hz) and high, delta-band (0.4-4.0Hz) frequency bands using GCaMP6 and hemodynamic contrasts. Homotopic GCaMP6 FC maps using delta-band data in the anesthetized states show a striking correlated and anti-correlated structure along the anterior to posterior axis. We next used whole-brain delay analysis to characterize this correlative feature. This structure is potentially explained by the observed propagation of delta-band activity from frontal somatomotor regions to visuoparietal areas, likely corresponding to propagating delta waves associated with slow wave sleep. During wakefulness, this spatio-temporal structure is largely absent, and a more complex and detailed FC structure is observed. Collectively, functional neuroimaging of calcium dynamics in mice provides evidence that spatiotemporal coherence in cortical activity is not exclusive to hemodynamics and exists over a larger range of frequencies than hemoglobin-based contrasts. Concurrent calcium and hemodynamic imaging enables direct temporal and functional comparison of spontaneous calcium and hemoglobin activity, effectively spanning neurovascular coupling and functional hyperemia. The combined calcium/hemoglobin imaging technique described here will enable the dissociation of changes in ionic and hemodynamic functional structure and provide a framework for subsequent studies of sleep disorders and neurological disease

Assessing Neuronal Synchrony and Brain Function Through Local Field Potential and Spike Analysis

Studies of neuronal network oscillations and rhythmic neuronal synchronization have led to a number of important insights in recent years, giving us a better understanding of the temporal organization of neuronal activity related to essential brain functions like sensory processing and cognition. Important principles and theories have emerged from these findings, including the communication through coherence hypothesis, which proposes that synchronous oscillations render neuronal communication effective, selective, and precise. The implications of such a theory may be universal for brain function, as the determinants of neuronal communication inextricably shape the neuronal representation of information in the brain. However, the study of communication through coherence is still relatively young. Since its articulation in 2005, the theory has predominantly been applied to assess cortical function and its communication with downstream targets in different sensory and behavioral conditions. The results herein are intended to bolster this hypothesis and explore new ways in which oscillations coordinate neuronal communication in distributed regions. This includes the development of new analytic tools for interpreting electrophysiological patterns, inspired by phase synchronization and spike train analysis. These tools aim to offer fast results with clear statistical and physiological interpretation

Changes in neuronal firing and synchrony precede recruitment of mesial temporal networks into generalizing seizures

Despite extensive study, the mechanisms underlying seizure generation and propagation are poorly understood. One approach is to study changes in the neuronal activity (of inhibitory and excitatory subpopulations) that occur during the recruitment of networks into a propagating seizure, to gain insight into mechanisms by which seizures spread across the brain. Recent work, comparing intra- and extracelluar recordings in ex-vivo preparations of human neocortex has implicated a failure in feed-forward inhibition underlying the spread of seizure. However, direct in-vivo study of inhibitory and excitatory population dynamics in the neocortex is difficult, due to an inability to separate single neuron activity into excitatory and inhibitory subpopulations. In the mesial temporal lobe (MTL) it is considerably easier to isolate these subpopulations, and several studies in the rodent MTL have, indeed, demonstrated an intricate spatiotemporal interplay between inhibitory and excitatory neuron firing and their corresponding synchrony to local field potentials during the transition to seizure. While this work suggests potential mechanisms for network recruitment into seizure, no direct observations have been made in the MTL of epileptic patients. This report provides methods to prolong the longevity of single neuron recordings in the human MTL. Using these recordings, evidence is presented that supports the hypothesis that recruitment of MTL networks into seizures of neocortical origin is preceded by specific spatiotemporal increases in synchrony. In detail, within the MTL there is a decrease in inhibitory interneuron firing that coincides with the inhibitory population becoming more coherent to their local field potentials. This increased synchrony between neurons and the local field occurs at frequencies similar to those of regional synchrony between MTL networks and the seizure focus. These results suggest a mechanism by which downstream networks are prepared for recruitment into generalizing seizures. Interestingly, these spatiotemporal changes occur prior to the first electrographic manifestation of seizure in the brain, implying that in addition to their role in seizure propagation, changes in interneuron firing and interneuron-field synchrony in the MTL may be reflective of early seizure activity in other brain structures as well, and may thus be a useful tool in developing improved early detection algorithms.Ph.D., Biomedical Engineering -- Drexel University, 201