Omar J. Ahmed

Thalamic Control of Layer 1 Circuits in Prefrontal Cortex

Knowledge of thalamocortical (TC) processing comes mainly from studying core thalamic systems that project to middle layers of primary sensory cortices. However, most thalamic relay neurons comprise a matrix of cells that are densest in the “nonspecific” thalamic nuclei and usually target layer 1 (L1) of multiple cortical areas. A longstanding hypothesis is that matrix TC systems are crucial for regulating neocortical excitability during changing behavioral states, yet we know almost nothing about the mechanisms of such regulation. It is also unclear whether synaptic and circuit mechanisms that are well established for core sensory TC systems apply to matrix TC systems. Here we describe studies of thalamic matrix influences on mouse prefrontal cortex using optogenetic and in vitro electrophysiology techniques. Channelrhodopsin-2 was expressed in midline and paralaminar (matrix) thalamic neurons, and their L1-projecting TC axons were activated optically. Contrary to conventional views, we found that matrix TC projections to L1 could transmit relatively strong, fast, high-fidelity synaptic signals. L1 TC projections preferentially drove inhibitory interneurons of L1, especially those of the late-spiking subtype, and often triggered feedforward inhibition in both L1 interneurons and pyramidal cells of L2/L3. Responses during repetitive stimulation were far more sustained for matrix than for core sensory TC pathways. Thus, matrix TC circuits appear to be specialized for robust transmission over relatively extended periods, consistent with the sort of persistent activation observed during working memory and potentially applicable to state-dependent regulation of excitability.

The hippocampal rate code: anatomy, physiology and theory

Since the days of Cajal, the CA1 pyramidal cell has arguably received more attention than any other neuron in the mammalian brain. Hippocampal CA1 pyramidal cells fire spikes with remarkable spatial and temporal precision, giving rise to the hippocampal rate and temporal codes. However, little is known about how different inputs interact during spatial behavior to generate such robust firing patterns. Here, we review the properties of the rodent hippocampal rate code and synthesize work from several disciplines to understand the functional anatomy and excitation-inhibition balance that can produce the rate-coded outputs of the CA1 pyramidal cell. We argue that both CA3 and entorhinal inputs are crucial for the formation of sharp, sparse CA1 place fields and that precisely timed and dominant inhibition is an equally important factor.

Running Speed Alters the Frequency of Hippocampal Gamma Oscillations

Successful spatial navigation is thought to employ a combination of at least two strategies: the following of landmark cues and path integration. Path integration requires that the brain use the speed and direction of movement in a meaningful way to continuously compute the position of the animal. Indeed, the running speed of rats modulates both the firing rate of neurons and the spectral properties of low frequency, theta oscillations seen in the local field potential (LFP) of the hippocampus, a region important for spatial memory formation. Higher frequency, gamma-band LFP oscillations are usually associated with decision-making, increased attention, and improved reaction times. Here, we show that increased running speed is accompanied by large, systematic increases in the frequency of hippocampal CA1 network oscillations spanning the entire gamma range (30–120 Hz) and beyond. These speed-dependent changes in frequency are seen on both linear tracks and two-dimensional platforms, and are thus independent of the behavioral task. Synchrony between anatomically distant CA1 regions also shifts to higher gamma frequencies as running speed increases. The changes in frequency are strongly correlated with changes in the firing rates of individual interneurons, consistent with models of gamma generation. Our results suggest that as a rat runs faster, there are faster gamma frequency transitions between sequential place cell-assemblies. This may help to preserve the spatial specificity of place cells and spatial memories at vastly different running speeds.

Single Neuron Activity and Theta Modulation in Postrhinal Cortex during Visual Object Discrimination

Postrhinal cortex, rodent homolog of the primate parahippocampal cortex, processes spatial and contextual information. Our hypothesis of postrhinal function is that it serves to encode context, in part, by forming representations that link objects to places. To test this hypothesis, we recorded postrhinal neurons and local field potentials (LFPs) in rats trained on a two-choice, visual discrimination task. As predicted, many postrhinal neurons signaled object-location conjunctions. Another large proportion encoded egocentric motor responses. In addition, postrhinal LFPs exhibited strong oscillatory rhythms in the theta band, and many postrhinal neurons were phase locked to theta. Although correlated with running speed, theta power was lower than predicted by speed alone immediately before and after choice. However, theta power was significantly increased following incorrect decisions, suggesting a role in signaling error. These findings provide evidence that postrhinal cortex encodes representations that link objects to places and suggest postrhinal theta modulation extends to cognitive as well as spatial functions.

Optogenetic Delay of Status Epilepticus Onset in an In Vivo Rodent Epilepsy Model

Epilepsy is a devastating disease, currently treated with medications, surgery or electrical stimulation. None of these approaches is totally effective and our ability to control seizures remains limited and complicated by frequent side effects. The emerging revolutionary technique of optogenetics enables manipulation of the activity of specific neuronal populations in vivo with exquisite spatiotemporal resolution using light. We used optogenetic approaches to test the role of hippocampal excitatory neurons in the lithium-pilocarpine model of acute elicited seizures in awake behaving rats. Hippocampal pyramidal neurons were transduced in vivo with a virus carrying an enhanced halorhodopsin (eNpHR), a yellow light activated chloride pump, and acute seizure progression was then monitored behaviorally and electrophysiologically in the presence and absence of illumination delivered via an optical fiber. Inhibition of those neurons with illumination prior to seizure onset significantly delayed electrographic and behavioral initiation of status epilepticus, and altered the dynamics of ictal activity development. These results reveal an essential role of hippocampal excitatory neurons in this model of ictogenesis and illustrate the power of optogenetic approaches for elucidation of seizure mechanisms. This early success in controlling seizures also suggests future therapeutic avenues.

A biologically constrained, mathematical model of cortical wave propagation preceding seizure termination.

Epilepsy—the condition of recurrent, unprovoked seizures—manifests in brain voltage activity with characteristic spatiotemporal patterns. These patterns include stereotyped semi-rhythmic activity produced by aggregate neuronal populations, and organized spatiotemporal phenomena, including waves. To assess these spatiotemporal patterns, we develop a mathematical model consistent with the observed neuronal population activity and determine analytically the parameter configurations that support traveling wave solutions. We then utilize high-density local field potential data recorded in vivo from human cortex preceding seizure termination from three patients to constrain the model parameters, and propose basic mechanisms that contribute to the observed traveling waves. We conclude that a relatively simple and abstract mathematical model consisting of localized interactions between excitatory cells with slow adaptation captures the quantitative features of wave propagation observed in the human local field potential preceding seizure termination.

Slow spatial recruitment of neocortex during secondarily generalized seizures and its relation to surgical outcome

Understanding the spatiotemporal dynamics of brain activity is crucial for inferring the underlying synaptic and nonsynaptic mechanisms of brain dysfunction. Focal seizures with secondary generalization are traditionally considered to begin in a limited spatial region and spread to connected areas, which can include both pathological and normal brain tissue. The mechanisms underlying this spread are important to our understanding of seizures and to improve therapies for surgical intervention. Here we study the properties of seizure recruitment—how electrical brain activity transitions to large voltage fluctuations characteristic of spike-and-wave seizures. We do so using invasive subdural electrode arrays from a population of 16 patients with pharmacoresistant epilepsy. We find an average delay of ∼30 s for a broad area of cortex (8 × 8 cm) to be recruited into the seizure, at an estimated speed of ∼4 mm/s. The spatiotemporal characteristics of recruitment reveal two categories of patients: one in which seizure recruitment of neighboring cortical regions follows a spatially organized pattern consistent from seizure to seizure, and a second group without consistent spatial organization of activity during recruitment. The consistent, organized recruitment correlates with a more regular, compared with small-world, connectivity pattern in simulation and successful surgical treatment of epilepsy. We propose that an improved understanding of how the seizure recruits brain regions into large amplitude voltage fluctuations provides novel information to improve surgical treatment of epilepsy and highlights the slow spread of massive local activity across a vast extent of cortex during seizure.

Dynamics of Propofol-Induced Loss of Consciousness Across Primate Neocortex

The precise neural mechanisms underlying transitions between consciousness and anesthetic-induced unconsciousness remain unclear. Here, we studied intracortical neuronal dynamics leading to propofol-induced unconsciousness by recording single-neuron activity and local field potentials directly in the functionally interconnecting somatosensory (S1) and frontal ventral premotor (PMv) network during a gradual behavioral transition from full alertness to loss of consciousness (LOC) and on through a deeper anesthetic level. Macaque monkeys were trained for a behavioral task designed to determine the trial-by-trial alertness and neuronal response to tactile and auditory stimulation. We show that disruption of coherent beta oscillations between S1 and PMv preceded, but did not coincide with, the LOC. LOC appeared to correspond to pronounced but brief gamma-/high-beta-band oscillations (lasting ∼3 min) in PMv, followed by a gamma peak in S1. We also demonstrate that the slow oscillations appeared after LOC in S1 and then in PMv after a delay, together suggesting that neuronal dynamics are very different across S1 versus PMv during LOC. Finally, neurons in both S1 and PMv transition from responding to bimodal (tactile and auditory) stimulation before LOC to only tactile modality during unconsciousness, consistent with an inhibition of multisensory integration in this network. Our results show that propofol-induced LOC is accompanied by spatiotemporally distinct oscillatory neuronal dynamics across the somatosensory and premotor network and suggest that a transitional state from wakefulness to unconsciousness is not a continuous process, but rather a series of discrete neural changes. SIGNIFICANCE STATEMENT How information is processed by the brain during awake and anesthetized states and, crucially, during the transition is not clearly understood. We demonstrate that neuronal dynamics are very different within an interconnecting cortical network (primary somatosensory and frontal premotor area) during the loss of consciousness (LOC) induced by propofol in nonhuman primates. Coherent beta oscillations between these regions are disrupted before LOC. Pronounced but brief gamma-band oscillations appear to correspond to LOC. In addition, neurons in both of these cortices transition from responding to both tactile and auditory stimulation before LOC to only tactile modality during unconsciousness. We demonstrate that propofol-induced LOC is accompanied by spatiotemporally distinctive neuronal dynamics in this network with concurrent changes in multisensory processing.

Finding synchrony in the desynchronized EEG: the history and interpretation of gamma rhythms

Neocortical gamma (30–80 Hz) rhythms correlate with attention, movement and perception and are often disrupted in neurological and psychiatric disorders. Gamma primarily occurs during alert brain states characterized by the so-called “desynchronized” EEG. Is this because gamma rhythms are devoid of synchrony? In this review we take a historical approach to answering this question. Richard Caton and Adolf Beck were the first to report the rhythmic voltage fluctuations in the animal brain. They were limited by the poor amplification of their early galvanometers. Thus when they presented light or other stimuli, they observed a disappearance of the large resting oscillations. Several groups have since shown that visual stimuli lead to low amplitude gamma rhythms and that groups of neurons in the visual cortices fire together during individual gamma cycles. This synchronous firing can more strongly drive downstream neurons. We discuss how gamma-band synchrony can support ongoing communication between brain regions, and highlight an important fact: there is at least local neuronal synchrony during gamma rhythms. Thus, it is best to refer to the low amplitude, high frequency EEG as an “activated”, not “desynchronized”, EEG.

Inhibitory single neuron control of seizures and epileptic traveling waves in humans

Inhibitory neuronal activity is critical for the normal functioning of the brain, but is thought to go awry during neurological disorders such as epilepsy. Animal models have suggested both decreased and increased inhibition as possible initiators of epileptic activity, but it is not known if, or how, human inhibitory neurons shape seizures. Here, using large-scale recordings of neocortical single neurons in patients with secondarily generalized tonic-clonic seizures, we show that fast-spiking (FS) inhibitory activity first increases as a seizure spreads across the neocortex, impeding and altering the spatial flow of fast epileptic traveling waves. Unexpectedly, however, FS cells cease firing less than half-way through a seizure. We use biophysically-realistic computational models to show that this cessation is due to FS cells entering depolarization block as a result of extracellular potassium accumulation during the seizure and not because they are inhibited by other inhibitory subtypes. Strikingly, this absence of FS inhibitory activity is accompanied by dramatic increases in local seizure amplitude along with unobstructed traveling waves and is seen during all secondarily generalized seizures examined, independent of etiology or focus. FS cessation also leads to prominent spike-and-wave events, suggesting that FS cell dynamics control the transition between the tonic and clonic phases of these seizures. Thus, it may be possible to curtail human seizures by preventing inhibitory neurons from entering potassium-dependent depolarization block, a novel and potentially powerful therapeutic avenue in treating multiple kinds of epilepsies.