Taufik A. Valiante

Dynamic circuit motifs underlying rhythmic gain control, gating and integration

Brain circuitry processes information by rapidly and selectively engaging functional neuronal networks. The dynamic formation of networks is often evident in rhythmically synchronized neuronal activity and tightly correlates with perceptual, cognitive and motor performances. But how synchronized neuronal activity contributes to network formation and how it relates to the computation of behaviorally relevant information has remained difficult to discern. Here we structure recent empirical advances that link synchronized activity to the activation of so-called dynamic circuit motifs. These motifs explicitly relate (1) synaptic and cellular properties of circuits to (2) identified timescales of rhythmic activation and to (3) canonical circuit computations implemented by rhythmically synchronized circuits. We survey the ubiquitous evidence of specific cell and circuit properties underlying synchronized activity across theta, alpha, beta and gamma frequency bands and show that their activation likely implements gain control, context-dependent gating and state-specific integration of synaptic inputs. This evidence gives rise to the dynamic circuit motifs hypothesis of synchronized activation states, with its core assertion that activation states are linked to uniquely identifiable local circuit structures that are recruited during the formation of functional networks to perform specific computational operations.

Transition to Seizure: Ictal Discharge Is Preceded by Exhausted Presynaptic GABA Release in the Hippocampal CA3 Region

How the brain transitions into a seizure is poorly understood. Recurrent seizure-like events (SLEs) in low-Mg2+/high-K+ perfusate were measured in the CA3 region of the intact mouse hippocampus. The SLE was divided into a “preictal phase,” which abruptly turns into a higher frequency “ictal” phase. Blockade of GABAA receptors shortened the preictal phase, abolished interictal bursts, and attenuated the slow preictal depolarization, with no effect on the ictal duration, whereas SLEs were blocked by glutamate receptor blockade. In CA3 pyramidal cells and stratum oriens non-fast-spiking and fast-spiking interneurons, recurrent GABAergic IPSCs predominated interictally and during the early preictal phase, synchronous with extracellularly measured recurrent field potentials (FPs). These IPSCs then decreased to zero or reversed polarity by the onset of the higher-frequency ictus. However, postsynaptic muscimol-evoked GABAA responses remained intact. Simultaneously, EPSCs synchronous with the FPs markedly increased to a maximum at the ictal onset. The reversal potential of the compound postsynaptic currents (combined simultaneous EPSCs and IPSCs) became markedly depolarized during the preictal phase, whereas the muscimol-evoked GABAA reversal potential remained unchanged. During the late preictal phase, interneuronal excitability was high, but IPSCs, evoked by local stimulation, or osmotically by hypertonic sucrose application, were diminished, disappearing at the ictal onset. We conclude that the interictal and early preictal states are dominated by GABAergic activity, with the onset of the ictus heralded by exhaustion of presynaptic release of GABA, and unopposed increased glutamatergic responses.

Burst Firing Synchronizes Prefrontal and Anterior Cingulate Cortex during Attentional Control

BACKGROUNDnIt is widely held that single cells in anterior cingulate and lateral prefrontal cortex (ACC/PFC) coordinate their activity during attentional processes, although cellular activity that may underlie such coordination across ACC/PFC has notxa0been identified. We thus recorded cells in five ACC/PFC subfields of macaques engaged in a selective attention task, characterized those spiking events that indexed attention, and identified how spiking of distinct cell populations synchronized between brain areas.nnnRESULTSnWe found that cells in ACC/PFC increased the firing of brief 200xa0Hz spike bursts when subjects shifted attention and engaged in selective visual processing. In contrast to nonburst spikes, burst spikes synchronized over large distances to local field potentials at narrow beta (12-20xa0Hz) and at gamma (50-75xa0Hz) frequencies. Long-range burst synchronization was anatomically specific, functionally connecting those subfields in area 24 (ACC) and area 46 (PFC) that are key players of attentional control. By splitting cells into putative excitatory (pE) and inhibitory (pI) cells by their broad and narrow spikes, we identified that bursts of pI cells preceded and that bursts of pE cells followed in time periods of maximal beta coherent network activity. In contrast, gamma bursts were transient impulses with equal timing across cell classes.nnnCONCLUSIONSnThese findings suggest that processes underlying burst firing and burst synchronization are candidate mechanisms to coordinate attention information across brain areas. We speculate that distinct burst-firing motifs realize beta andxa0gamma synchrony to trigger versus maintain functional network states during goal-directed behavior.

Saccades during visual exploration align hippocampal 3-8 Hz rhythms in human and non-human primates.

Visual exploration in primates depends on saccadic eye movements (SEMs) that cause alternations of neural suppression and enhancement. This modulation extends beyond retinotopic areas, and is thought to facilitate perception; yet saccades may also influence brain regions critical for forming memories of these exploratory episodes. The hippocampus, for example, shows oscillatory activity that is generally associated with encoding of information. Whether or how hippocampal oscillations are influenced by eye movements is unknown. We recorded the neural activity in the human and macaque hippocampus during visual scene search. Across species, SEMs were associated with a time-limited alignment of a low-frequency (3–8 Hz) rhythm. The phase alignment depended on the task and not only on eye movements per se, and the frequency band was not a direct consequence of saccade rate. Hippocampal theta-frequency oscillations are produced by other mammals during repetitive exploratory behaviors, including whisking, sniffing, echolocation, and locomotion. The present results may reflect a similar yet distinct primate homologue supporting active perception during exploration.

Histologically Confirmed Hippocampal Structural Features Revealed by 3T MR Imaging: Potential to Increase Diagnostic Specificity of Mesial Temporal Sclerosis

BACKGROUND AND PURPOSE: With appropriate selection, temporal lobe epilepsy is potentially curable with surgical intervention achieving seizure freedom in ∼80% of individuals. MR imaging−based identification of MTS remains central to the selection process but currently relies on qualitative visual analysis. We sought to determine if new ultrastructural hippocampal details seen on 3T MR imaging had histopathologic correlates and whether these could serve as a useful tool in MTS identification. MATERIALS AND METHODS: Patients undergoing selective anterior temporal lobectomy (n = 5) were scanned using 3T MR imaging preoperatively. En bloc resections were rescanned and subsequently prepared for histopathologic analysis of all hippocampal layers in the CA1–3 regions. Using a newly identified landmark from 3T FSTIR coronal images in 20 patients with histologically confirmed MTS, blinded studies compared ipsilateral and contralateral sides to generate threshold measurements for application in a fast quantitative analysis tool. RESULTS: Histopathologic analysis and correlation with 3T imaging of en bloc resections identified the low-intensity signal as the stratum lacunosum. MTS was associated with extensive gliosis throughout the CA1–3 regions, with loss of tissue thickness in the stratum pyramidale most pronounced in CA1. Fast quantitative analysis by using the stratum lacunosum as a landmark provided a test that identifies MTS with a SN of 70% and SP of 85%. CONCLUSIONS: Here we delineated ultrastructural hippocampal details seen on 3T MR imaging in both the in vivo and ex vivo setting, correlating these with histopathologic features consistent with MTS, and provided preliminary data suggesting their utility in the development of a quantitative analysis assessment tool for application in surgical-candidate selection.

In Vitro Recordings of Human Neocortical Oscillations

Electrophysiological oscillations are thought to create temporal windows of communication between brain regions. We show here that human cortical slices maintained in vitro can generate oscillations similar to those observed in vivo. We have characterized these oscillations using local field potential and whole-cell recordings obtained from neocortical slices acquired during epilepsy surgery. We confirmed that such neocortical slices maintain the necessary cellular and circuitry components, and in particular inhibitory mechanisms, to manifest oscillatory activity when exposed to glutamatergic and cholinergic agonists. The generation of oscillations was dependent on intact synaptic activity and muscarinic receptors. Such oscillations differed in electrographic and pharmacological properties from epileptiform activity. Two types of activity, theta oscillations and high gamma activity, uniquely characterized this model-activity not typically observed in animal cortical slices. We observed theta oscillations to be synchronous across cortical laminae suggesting a novel role of theta as a substrate for interlaminar communication. As well, we observed cross-frequency coupling (CFC) between theta phase and high gamma amplitude similar to that observed in vivo. The high gamma bursts generated by such CFC varied in their frequency content, suggesting that this variability may underlie the broadband nature of high gamma activity.

Transition to seizure: From “macro”- to “micro”-mysteries

One of the most terrifying aspects of epilepsy is the sudden and apparently unpredictable transition of the brain into the pathological state of an epileptic seizure. The pathophysiology of the transition to seizure still remains mysterious. Herein we review some of the key concepts and relevant literatures dealing with this enigmatic transitioning of brain states. At the MACRO level, electroencephalographic (EEG) recordings at time display preictal phenomena followed by pathological high-frequency oscillations at the seizure onset. Numerous seizure prediction algorithms predicated on identifying changes prior to seizure onset have met with little success, underscoring our lack of understanding of the dynamics of transition to seizure, amongst other inherent limitation. We then discuss the concept of synchronized hyperexcited oscillatory networks underlying seizure generation. We consider these networks as weakly coupled oscillators, a concept which forms the basis of some relevant mathematical modeling of seizure transitions. Next, the underlying MICRO processes involved in seizure generation are discussed. The depolarization of the GABA(A) chloride reversal potential is a major concept, facilitating epileptogenesis, particularly in immature brain. Also the balance of inhibitory and excitatory local neuronal networks plays an important role in the process of transitioning to seizure. Gap junctional communication, including that which occurs between glia, as well as ephaptic interactions are increasingly recognized as critical for seizure generation. In brief, this review examines the evidence regarding the characterization of the transition to seizure at both the MACRO and MICRO levels, trying to characterize this mysterious yet critical problem of the brain state transitioning into a seizure.

Phase–Amplitude Coupling and Interlaminar Synchrony Are Correlated in Human Neocortex

One of the striking manifestations of neuronal population activity is that of rhythmic oscillations in the local field potential. It is thought that such oscillatory patterns, including phase-amplitude coupling (PAC) and inter-regional synchrony, may represent forms of local and long-range cortical computations, respectively. Although it has been speculated that these two oscillatory patterns are functionally related, and bind disparate cortical assemblies to one another at different timescales, there is little direct evidence to support this hypothesis. We have demonstrated recently that theta to high-gamma PAC and interlaminar phase coherence at theta frequencies can be generated in human cortical slices maintained in vitro. Here we show that not only do such oscillatory patterns exist within human temporal neocortex, but that the strength of one is related to the strength of the other. We demonstrate that at theta frequencies, metrics of temporal synchrony between superficial and deep cortical laminae (phase-dependent power correlations, and phase coherence) are correlated to the magnitude of intralaminar PAC between theta and high-gamma. Specifically, our results suggest that interlaminar communication within human temporal neocortex and local laminar excitability are linked to one another through a dependence mediated by theta oscillations. More generally, our results provide evidence for the hypothesis that theta oscillations may coordinate inter-areal excitability in the human brain.

Complexity and multifractality of neuronal noise in mouse and human hippocampal epileptiform dynamics

Fractal methods offer an invaluable means of investigating turbulent nonlinearity in non-stationary biomedical recordings from the brain. Here, we investigate properties of complexity (i.e. the correlation dimension, maximum Lyapunov exponent, 1/f(γ) noise and approximate entropy) and multifractality in background neuronal noise-like activity underlying epileptiform transitions recorded at the intracellular and local network scales from two inxa0vitro models: the whole-intact mouse hippocampus and lesional human hippocampal slices. Our results show evidence for reduced dynamical complexity and multifractal signal features following transition to the ictal epileptiform state. These findings suggest that pathological breakdown in multifractal complexity coincides with loss of signal variability or heterogeneity, consistent with an unhealthy ictal state that is far from the equilibrium of turbulent yet healthy fractal dynamics in the brain. Thus, it appears that background noise-like activity successfully captures complex and multifractal signal features that may, at least in part, be used to classify and identify brain state transitions in the healthy and epileptic brain, offering potential promise for therapeutic neuromodulatory strategies for afflicted patients suffering from epilepsy and other related neurological disorders.

Determining surgical candidacy in temporal lobe epilepsy.

Temporal lobe epilepsy (TLE) is the most common form of adult epilepsy that is amenable to surgical treatment. In the carefully selected patient, excellent seizure outcome can be achieved with minimal or no side effects from surgery. This may result in improved psychosocial functioning, achieving higher education, and maintaining or gaining employment. The objective of this paper is to discuss the surgical selection process of a patient with TLE. We define what constitutes a patient that has medically refractory TLE, describe the typical history and physical examination, and distinguish between mesial TLE and neocortical TLE. We then review the role of routine (ambulatory/sleep-deprived electroencephalography (EEG), video EEG, magnetic resonance imaging (MRI), neuropsychological testing, and Wada testing) and ancillary preoperative testing (positron emission tomography, single-photon emission computed tomography (SPECT), subtraction ictal SPECT correlated to MRI (SISCOM), magnetoencephalography, magnetic resonance spectroscopy, and functional MRI) in selecting surgical candidates. We describe the surgical options for resective epilepsy surgery in TLE and its commonly associated risks while highlighting some of the controversies. Lastly, we present teaching cases to illustrate the presurgical workup of patients with medically refractory TLE.