Biology subjects

Smith, E. H.

Publications and source records attributed to Smith, E. H..

26 records · Page 2Linked to original sources

bioRxiv2020

A spatially-tracked single cell transcriptomics map of neuronal networks in the intrinsic cardiac nervous system

We developed a spatially-tracked single neuron transcriptomics map of an intrinsic cardiac ganglion - the right atrial ganglionic plexus (RAGP) that is a critical mediator of vagal control of the sinoatrial node (SAN) activity. We developed a 3D representation of RAGP with extensive mapping of neurons and used neuronal tracing to identify the spatial distribution of the subset of neurons that project to the SAN. RNAseq of laser capture microdissected neurons revealed a distinct composition of RAGP neurons compared to CNS neuronal subtypes. High-throughput qPCR of hundreds of laser capture microdissected single neurons led to a surprising finding that cholinergic and catecholaminergic neuronal markers Th and Chat were correlated, suggesting multipotential phenotypes that can drive neuroplasticity within RAGP. Interestingly, no single gene or module was an exclusive marker of RAGP neuronal connectivity to SAN. Neuropeptide-receptor coexpression analysis revealed a combinatorial paracrine neuromodulatory network within RAGP, informing follow-on studies on the vagal control of RAGP to regulate cardiac function in health and disease.

neuroscience↗

bioRxiv2020

Dual mechanisms of ictal high frequency oscillations in human rhythmic onset seizures

High frequency oscillations (HFOs) recorded from intracranial electrodes during epileptiform discharges are a proposed biomarker of epileptic brain tissue and may also be useful for seizure forecasting, with mixed results. Despite such potential for HFOs, there is limited investigation into the spatial context of HFOs and their relationship to simultaneously recorded neuronal activity. We sought to further understand the biophysical underpinnings of ictal HFOs using unit recordings in the human neocortex and mesial temporal lobe during rhythmic onset seizures. We compare features of ictal discharges in both the seizure core and penumbra (spatial seizure domains defined by multiunit activity patterns). We report differences in spectral features, unit-local field potential coupling, and information theoretic characteristics of HFOs before and after local seizure invasion. Furthermore, we tie these timing-related differences to spatial domains of seizures, showing that penumbral discharges are widely distributed and less useful for seizure localization.

physiology↗

bioRxiv2020

Neuronal firing and waveform alterations through ictal recruitment in humans

AO_SCPLOWBSTRACTC_SCPLOWClinical analyses of neuronal activity during seizures, invariably using extracellular recordings, is greatly hindered by various phenomena that are well established in animal studies: changes in local ionic concentration, changes in ionic conductance, and intense, hypersynchronous firing. The first two alter the action potential waveform, whereas the third increases the "noise"; all three factors confound attempts to detect and classify single neurons (units). To address these analytical difficulties, we developed a novel template-matching based spike sorting method, which enabled identification of 1,239 single units in 27 patients with intractable focal epilepsy, that were tracked throughout multiple seizures. These new analyses showed continued neuronal firing through the ictal transition, which was defined as a transient period of intense tonic firing consistent with previous descriptions of the ictal wavefront. After the ictal transition, neurons displayed increased spike duration (p < 0.001) and reduced spike amplitude (p < 0.001), in keeping with prior animal studies; units in non-recruited territories, by contrast, showed more stable waveforms. All units returned to their pre-ictal waveforms after seizure termination. Waveshape changes were stereotyped across seizures within patients. Our analyses of single neuron firing patterns, at the ictal wavefront, showed widespread intense activation, and commonly involving marked waveshape alteration. We conclude that the distinction between tissue that has been recruited to the seizure versus non-recruited territories is evident at the level of single neurons, and that increased waveform duration and decreased waveform amplitude are hallmarks of seizure invasion that could be used as defining characteristics of local recruitment. SO_SCPLOWIGNIFICANCEC_SCPLOW SO_SCPLOWTATEMENTC_SCPLOWAnimal studies consistently show marked changes in action potential waveform during epileptic discharges, but acquiring similar evidence in humans has proved difficult. Assessing neuronal involvement in ictal events is pivotal to understanding seizure dynamics and in defining clinical localization of epileptic pathology. Using a novel method to track neuronal firing, we analyzed microelectrode array recordings of spontaneously occurring human seizures, and here report two dichotomous activity patterns. In cortex that is recruited to the seizure, neuronal firing rates increase and waveforms become longer in duration and shorter in amplitude, while penumbral tissue shows stable action potentials, in keeping with the "dual territory" model of seizure dynamics.

neuroscience↗

bioRxiv2019

A theoretical model for focal seizure initiation, propagation, termination, and progression

We developed a neural network model that can account for the major elements common to human focal seizures. These include the tonic-clonic transition, slow advance of clinical semiology and corresponding seizure territory expansion, widespread EEG synchronization, and slowing of the ictal rhythm as the seizure approaches termination. These were reproduced by incorporating usage-dependent exhaustion of inhibition in an adaptive neural network that receives global feedback inhibition in addition to local recurrent projections. Our model proposes mechanisms that may underline common EEG seizure onset patterns and status epilepticus and postulates a role for synaptic plasticity in emergence of epileptic foci. Complex patterns of seizure activity and bi-stable seizure evolution end-points arise when stochastic noise is included. With the rapid advancement of clinical and experimental tools, we believe that this can provide a roadmap and potentially a testbed for future explorations of seizure mechanisms and clinical therapies.

neuroscience↗

bioRxiv2019

Single-neuron representations of spatial memory targets in humans

The hippocampus and surrounding medial-temporal-lobe (MTL) structures are critical for both memory and spatial navigation, but we do not fully understand the neuronal representations used to support these behaviors. Much research has examined how the MTL neurally represents spatial information, such as with \"place cells\" that represent the current location or \"head-direction cells\" that code for the current heading. In addition to behaviors that require an animal to attend to the current spatial location, navigating to remote destinations is a common part of daily life. To examine the neural basis of these behaviors we recorded single-neuron activity from neurosurgical patients playing Treasure Hunt, a virtual-reality spatial-memory task. By analyzing how the activity of these neurons related to behavior in Treasure Hunt, we found that the firing rates of many MTL neurons during navigation significantly changed depending on the position of the current spatial target. In addition, we observed neurons whose firing rates during navigation were tuned to specific heading directions in the environment, and others whose activity changed depending on the timing within the trial. By showing that neurons in our task represent remote locations rather than the subjects own position, our results suggest that the human MTL can represent remote spatial information according to task demands.

neuroscience↗

bioRxiv2018

Functionally distinct high and low theta oscillations in the human hippocampus

Based on rodent models, researchers have theorized that the hippocampus supports episodic memory and navigation via the theta oscillation, a ~4-10-Hz rhythm that coordinates brain-wide neural activity. However, recordings from humans have indicated that hippocampal theta oscillations are lower in frequency and less prevalent than in rodents, suggesting interspecies differences in thetas function. To characterize human hippocampal theta, we examined the properties of theta oscillations throughout the anterior-posterior length of the hippocampus as neurosurgical subjects performed a virtual spatial navigation task. During virtual movement, we observed hippocampal oscillations at multiple frequencies from 2 to 14 Hz. The posterior hippocampus prominently displayed oscillations at ~8-Hz and the precise frequency of these oscillations correlated with the speed of movement, implicating these signals in spatial navigation. We also observed slower ~3-Hz oscillations, but these signals were more prevalent in the anterior hippocampus and their frequency did not vary with movement speed. Our results converge with recent findings to suggest an updated view of human hippocampal electrophysiology. Rather than one hippocampal theta oscillation with a single general role, high-and low-theta oscillations, respectively, may reflect spatial and non-spatial cognitive processes.

neuroscience↗

bioRxiv2018

Single neurons in the human entorhinal cortex remap to distinguish individual spatial memories

The entorhinal cortex (EC) is known to play a key role in both memory and spatial navigation. Despite this overlap in spatial and mnemonic circuits, it is unknown how spatially responsive neurons contribute to our ability to represent and distinguish past experiences. Recording from medial temporal lobe (MTL) neurons in subjects performing cued recall of object-location memories in a virtual-reality environment, we identified \"trace cells\" in the EC that remap their spatial fields to locations subjects were cued to recall on each trial. In addition to shifting its firing field according to the memory cue, this neuronal activity exhibited a firing rate predictive of the cued memorys content. Critically, this memory-specific neuronal activity re-emerged when subjects were cued for recall without entering the environment, indicating that trace-cell memory representations generalized beyond navigation. These findings suggest a general mechanism for memory retrieval via trace-cell activity and remapping in the EC.

neuroscience↗

bioRxiv2018

Reduced repertoire of cortical microstates and neuronal ensembles in medically-induced loss of consciousness

Medically-induced loss of consciousness (mLOC) has been linked to a macroscale break-down of brain connectivity, yet the neural microcircuit correlates of mLOC remain unknown. We applied non-linear t-stochastic neighbor embedding (t-SNE) and Lempel-Ziv-Welch complexity analysis to two-photon calcium imaging and local field potential (LFP) measurements of cortical microcircuit activity across anesthetic depth in mice, and to micro-electrode array recordings in human subjects. We find that mLOC disrupts population activity patterns by i) a reduction of discriminable network microstates and ii) a reduction of independent neuronal ensembles. These alterations are not explained by a simple reduction of neuronal activity and reveal abnormal functional microcircuits. Thus, normal neuronal ensemble dynamics could contribute to the emergence of conscious states.

neuroscience↗