Arousal fluctuations govern oscillatory transitions between dominant gamma and alpha occipital activity during eyes open/closed conditions

Arousal results in widespread activation of brain areas to increase their response in task and behavior relevant ways. Mediated by the Ascending Reticular Arousal System (ARAS), arousal-dependent inputs interact with neural circuitry to shape their dynamics. In the occipital cortex, such inputs may trigger shifts between dominant oscillations, where α activity is replaced by γ activity, or vice versa. A salient example of this are spectral power alternations observed while eyes are opened and/or closed. These transitions closely follow fluctuations in arousal, suggesting a common origin.To better understand the mechanisms at play, we developed and analyzed a computational model composed of two modules: a thalamocortical feedback circuit coupled with a superficial cortical network. Upon activation by noise-like inputs originating from the ARAS, our model is able to demonstrate that noise-driven nonlinear interactions mediate transitions in dominant peak frequency, resulting in the simultaneous suppression of α limit cycle activity and the emergence of γ oscillations through coherence resonance. Reduction in input provoked the reverse effect-leading to anticorrelated transitions between α and γ power. Taken together, these results shed a new light on how arousal shapes oscillatory brain activity

At clinically relevant concentrations the anaesthetic/amnesic thiopental but not the anticonvulsant phenobarbital interferes with hippocampal sharp wave-ripple complexes

<p>Abstract</p> <p>Background</p> <p>Many sedative agents, including anesthetics, produce explicit memory impairment by largely unknown mechanisms. Sharp-wave ripple (SPW-R) complexes are network activity thought to represent the neuronal substrate for information transfer from the hippocampal to neocortical circuits, contributing to the explicit memory consolidation. In this study we examined and compared the actions of two barbiturates with distinct amnesic actions, the general anesthetic thiopental and the anticonvulsant phenobarbital, on in vitro SPW-R activity.</p> <p>Results</p> <p>Using an in vitro model of SPW-R activity we found that thiopental (50–200 μM) significantly and concentration-dependently reduced the incidence of SPW-R events (it increased the inter-event period by 70–430 %). At the concentration of 25 μM, which clinically produces mild sedation and explicit memory impairment, thiopental significantly reduced the quantity of ripple oscillation (it reduced the number of ripples and the duration of ripple episodes by 20 ± 5%, n = 12, <it>P </it>< 0.01), and suppressed the rhythmicity of SPWs by 43 ± 15% (n = 6, <it>P </it>< 0.05). The drug disrupted the synchrony of SPWs within the CA1 region at 50 μM (by 19 ± 12%; n = 5, <it>P </it>< 0.05). Similar effects of thiopental were observed at higher concentrations. Thiopental did not affect the frequency of ripple oscillation at any of the concentrations tested (10–200 μM). Furthermore, the drug significantly prolonged single SPWs at concentrations ≥50 μM (it increased the half-width and the duration of SPWs by 35–90 %). Thiopental did not affect evoked excitatory synaptic potentials and its results on SPW-R complexes were also observed under blockade of NMDA receptors. Phenobarbital significantly accelerated SPWs at 50 and 100 μM whereas it reduced their rate at 200 and 400 μM. Furthermore, it significantly prolonged SPWs, reduced their synchrony and reduced the quantity of ripples only at the clinically very high concentration of 400 μM, reported to affect memory.</p> <p>Conclusion</p> <p>We hypothesize that thiopental, by interfering with SPW-R activity, through enhancement of the GABA_Areceptor-mediated transmission, affects memory processes which involve hippocampal circuit activation. The quantity but not the frequency of ripple oscillation was affected by the drug.</p

SLEEPING WHILE AWAKE: A NEUROPHYSIOLOGICAL INVESTIGATION ON SLEEP DURING WAKEFULNESS.

Il sonno e la veglia vengono comunemente considerati come due stati distinti. L\u2019alternanza tra essi, la cui presenza \ue8 stata dimostrata in ogni specie animale studiata fino ad oggi, sembra essere una delle caratteristiche che definisce la nostra vita. Allo stesso tempo, per\uf2, le scoperte portate alla luce negli ultimi decenni hanno offuscato i confini tra questi due stati. I meccanismi del sonno hanno sempre affascinato i neurofisiologi, che infatti, nell\u2019ultimo secolo, li hanno caratterizzati in dettaglio: ora sappiamo che all\u2019attivit\ue0 del sonno sottost\ue0 una specifica attivit\ue0 neuronale chiamata slow oscillation. La slow oscillation, che \ue8 costituita da (ancora una volta) un\u2019alternanza tra periodi di attivit\ue0 e periodi di iperpolarizzazione e silenzio neuronale (OFF-periods), \ue8 la modalit\ue0 base di attivazione del cervello dormiente. Questa alternanza \ue8 dovuta alla tendenza dei neuroni surante lo stato di sonno, di passare ad un periodo silente dopo un\u2019attivazione iniziale, una tendenza a cui viene dato il nome di bistabilit\ue0 neuronale. Molti studi hanno dimostrato come la bistabilit\ue0 neuronale tipica del sonno ed i relativi OFF-periods, possano accadere anche durante la veglia in particolari condizioni patologiche, nelle transizioni del sonno e durante le deprivazioni di sonno. Per questo motivo, se accettassimo che la bistabilit\ue0 neuronale e gli OFF-periods rappresentino una caratteristica fondamentale del sonno, allora dovremmo ammettere che stiamo assistendo ad un cambio di paradigma: da una prospettiva neurofisiologica il sonno pu\uf2 intrudere nella veglia. In questa tesi ho analizzato i nuovi -fluidi- confini tra sonno e veglia e le possibili implicazioni di questi nel problema della persistenza personale attraverso il tempo. Inoltre, ho studiato le implicazioni cliniche dell\u2019intrusione di sonno nella veglia in pazienti con lesioni cerebrali focali di natura ischemica. In particolare, i miei obiettivi sono stati: 1) Dimostrare come la bistabilit\ue0 neuronale possa essere responsabile della perdita di funzione nei pazienti affetti da ischemia cerebrale e come questo potrebbe avere implicazioni nello studio della patofisiologia dell\u2019ischemia cerebrale e nella sua terapia; 2) Stabilire le basi per un modello di sonno locale presente nella vita di tutti i giorni: la sensazione di sonnolenza. Infatti, essa potrebbe riflettere la presenza di porzioni di corteccia in stato di sonno, ma durante lo stato di veglia; 3) Difendere il criterio biologico di identit\ue0, che troverebbe nell\u2019attivit\ue0 cerebrale la continuit\ue0 necessaria al mantenimento della nostra identit\ue0 nel tempo.Sleep and wakefulness are considered two mutually exclusive states. The alternation between those two states seems to be a defining characteristic of our life, a ubiquitous phenomenon demonstrated in every animal species investigated so far. However, during the last decade, advances in neurophysiology have blurred the boundaries between those states. The mechanisms of sleep have always intrigued neurophysiologists and great advances have been made over the last century in understanding them: we now know that the defining characteristic underlying sleep activity is a specific pattern of neuronal activity, namely the slow oscillation. The slow oscillation, which is characterized by the periodic alternation between periods of activity (ON-periods) and periods of hyperpolarization and neuronal silence (OFF-periods) is the default mode of activity of the sleeping cortex. This alternation is due to the tendency of neurons to fall into a silent period after an initial activation; such tendency is known as \u201cbistability\u201d. There is accumulating evidence that sleep-like bistability, and the ensuing OFF-periods, may occur locally in the awake human brain in some pathological conditions, in sleep transition, as well as after sleep deprivation. Therefore, to the extent that bistability and OFF periods represents the basic neuronal features of sleep, a paradigm shift is in place: from a neurophysiological perspective sleep can intrude into wakefulness. In this thesis, I explore the fluid boundaries between sleep and wakefulness and investigate their possible implications on the problem of personal persistence over time. Moreover, I study the clinical implications of the intrusion of sleep into wakefulness in patients with focal brain injury due to stroke. Specifically, I aim to: 1) show how the sleep-like bistability can be responsible for the loss of function in stroke patients. This may have implications for understanding the pathophysiology of stroke and helping to foster recovery; 2) establish the basis for a model of local sleep that might be present in the everyday life, id est the sensation of sleepiness. Indeed, sleepiness could reflect islands of sleep during wakefulness; 3) advocate the biological criterion of identity, in which the continuity necessary for maintaining ourselves over time could be represented by never resting activity in the brain

Abnormal network oscillations in patients with Dementia with Lewy bodies and a mouse model of alpha-synucleinopathy

Ph. D. Thesis.Electrophysiology can reveal changes in neuronal oscillatory activity in the brain in relation to neurodegenerative disorders, including dementia with Lewy bodies (DLB). DLB, characterised by abnormal α-synuclein (α-syn) aggregation within neurons, is the second most common cause of dementia after Alzheimer’s disease (AD). This thesis had two aims. Firstly, to identify resting-state EEG changes that reflect cognitive fluctuations, a DLB core symptom, and differentiate DLB from AD and Parkinson’s disease dementia (PDD) patients and healthy controls. Secondly, to detect electrophysiological alterations in young mice over-expressing human mutant α-syn while under urethane-induced anaesthesia, mimicking deep-sleep. The resulting slowoscillation (SO) composed of Up-states (neuronal firing) and Down-states (neuronal “silence”), was recorded intra-cortically, from the hippocampus and medial prefrontal cortex (mPFC). The human EEG analysis replicated reports of a shift of power and dominant frequency (DF) from alpha to theta frequencies, in DLB/PDD patients compared to AD patients and controls. Contrary to previous work, the DF variability (DFV) over time was increased in AD and not in DLB/PDD patients, although a DLBspecific correlation between the DFV and cognitive fluctuations persisted. The DFV and power/DF distribution could differentiate between AD and DLB patients with high sensitivity (92.26%) and specificity (83.3%). Analysis of sleep patterns in α-syn mice in both the mPFC and hippocampus revealed increased SO frequency, aberrant neuronal firing activity on Down-states, altered power distribution on Up-states and disturbed sleep spindle activity, compared to WTs. A novel infra-slow modulation (ISM) was described in WTs, presenting as bursts of power across frequencies every ~ 3.5 min. In α-syn mice, the ISM induced abnormally high levels of high frequency oscillatory power in the hippocampus. Our findings indicate altered neuronal oscillatory activity in DLB patients and α-syn mice during rest and sleep respectively, suggesting that α-syn affects the integrity of the networks underlying widespread, synchronous activity.Alzheimer’s Societ

Investigating the role of Gamma-aminobutyric acid (GABA) in sedation: a combinedelectrophysiological, haemodynamicand spectroscopic study in humans

A better understanding of the mechanisms of anaesthesia and sedation are expected not only to improve the understanding of the neural correlates of consciousness but also to help improve safety from the complications of anaesthesia/ sedation and develop safer drugs and objective brain function monitoring systems. Neuroimaging modalities such as functional MRI, magnetoencephalography and MR spectroscopy provide complimentary information about brain functions and can help interrogate brain activity in a living human brain. Most anaesthetic drugs act by enhancing the inhibitory actions of GABA in the brain. Most neuroimaging research has focused on anaesthetic-induced unconsciousness, with only few investigating the earliest levels of sedation-induced altered consciousness. The work in this thesis used a range of advanced neuroimaging modalities to investigate the role of GABA (through a GABA-ergic drug, propofol), during mild sedation, in humans. This was performed as a series of experiments within two, sequential, scanning sessions, MEG followed by fMRI, in the same participants. Propofol resulted in a dissociation of the visual gamma band response (decreased evoked, increased induced power). This was related to a reduced BOLD fMRI response but there were no changes in MRS detectable GABA concentration. Response to multisensory stimulation also revealed interesting changes with MEG and fMRI. Functional connectivity analyses showed changes in connectivities of the posterior cingulate cortex (key hub of default-mode network) and thalamus with each other and other key brain regions. Resting state networks were identified with MEG too, which revealed interesting increases in connectivity in certain band- limited networks while motor networks showed no change. Perfusion fMRI using arterial spin labelling revealed a global and regional reduction in perfusion, highlighting some of the key regions (frontal cortex, precuenus, PCC and thalamus) involved in sedation

Loss of neuronal network resilience precedes seizures and determines the ictogenic nature of interictal synaptic perturbations

The mechanisms of seizure emergence, and the role of brief interictal epileptiform discharges (IEDs) in seizure generation are two of the most important unresolved issues in modern epilepsy research. Our study shows that the transition to seizure is not a sudden phenomenon,but a slow process characterized by the progressive loss of neuronal network resilience. From a dynamical perspective, the slow transition is governed by the principles of critical slowing, a robust natural phenomenon observable in systems characterized by transitions between dynamical regimes. In epilepsy, this process is modulated by the synchronous synaptic input from IEDs. IEDs are external perturbations that produce phasic changes in the slow transition process and exert opposing effects on the dynamics of a seizure-generating network, causing either anti-seizure or pro-seizure effects. We show that the multifaceted nature of IEDs is defined by the dynamical state of the network at the moment of the discharge occurrence

Studying spontaneous brain activity with neuroimaging methods and mathematical modelling

The study of spontaneous brain activity using functional Magnetic Resonance Imaging (fMRI) is a relatively young and rapidly developing field born in the mid-nineties. So far, sufficiently solid foundations have been established, mainly in validating the neuronal origin of a significant component of observed low-frequency fluctuations in the 'resting state' fMRI signal. Nevertheless, the field is still facing several major challenges. This thesis first reviews the current state of knowledge and subsequently proceeds to present original research results that are directed towards overcoming these challenges. The first challenge stems from the indirect nature of the fMRI recordings, obscuring the interpretation in terms of the underlying neuronal activity. Two investigations related to this are presented. First, I show that increased head-movement, epiphenomenal to altered states of consciousness, can lead to spurious increases in low-frequency fluctuations in fMRI signal. This may adversely affect inferences on the underlying neurophysiological processes. Second, I demonstrate a direct electrophysiological correlate of increased synchronisation of fMRI activity in areas of the much studied default-mode network. By directly studying electrophysiological correlates of fMRI-based functional connectivity, this study took a pioneering approach to confirming the biological validity of the fMRI functional connectivity concept. Another widely debated question within the field is the optimal method for extracting relevant information from the extreme volumes of neuroimaging data. I present an investigation providing insights and practical recommendations for this question, based on assessing the interdependence information neglected by the commonly used linear correlation for fMRI functional connectivity studies. The results suggest that in typical resting state data, the nonlinear contributions to instantaneous connectivity are negligible. The third major challenge of the field is the integration of the experimental evidence into theoretical models of spontaneous brain activity. In the last part of this thesis, such models are discussed in detail, focusing on the two crucial features of observed spontaneous brain activity: functional connectivity and low-frequency fluctuations. Two specific mechanisms for emergence of the latter are proposed, depending either on the local synchronisation dynamics or the regulatory action of particular neuromodulators. The thesis concludes with discussion of the questions arising from the presented results in the context of the most recent development in the wider field

Top-down and bottom-up control of drug-induced sleep and anaesthesia

In recent decades, research has unravelled fascinating detail about the molecular mechanisms underpinning pharmacologic loss of consciousness (LOC). However, the systems-level mechanisms are far less clear. Recent genetic approaches, however, enable unprecedented dissection on neural pathways, and they are paving a way for this line of research. The focus of this thesis is to investigate the neuroanatomical substrates of commonly used drugs which reversibly render us unconscious. Zolpidem is a positive allosteric modulator (PAM) of the GABAA receptor which binds to the benzodiazepine (BZ) site. Because zolpidem binds 1-3,,2 containing GABAA receptors, which are widespread, it acts virtually everywhere. We do not know if zolpidem causes sleep by enhancing GABAergic inhibition throughout the entire brain, or if the therapeutic sleep-inducing property depends upon specific brain circuitry. 2I77 mice are devoid of zolpidem-sensitivity. But, zolpidem-sensitivity can be restored selectively in brain regions, enabling dissection of the circuitry involved in zolpidem’s effect. To isolate the therapeutic effect of zolpidem we deleted GABAA-2I77-subunits and replaced them with GABAA-2F77-subunits in HDC neurons or frontal-cortex in isolation. We were able to selectively restore zolpidem-sensitivity in target neurons. This conferred zolpidem-enhanced IPSCs locally. Compared with wild-type mice and zolpidem-insensitive 2I77lox mice, we found that GABAA-2F77 receptors in either HDC-neurons or frontal cortex alone were enough to rescue the majority of zolpidem-mediated sleep. The response in HDC-2F77 mice was similar to that of an H1-receptor antagonist. By producing a null effect in a negative-control area – the superior colliculus – we show that HDC neurons and the frontal cortex are both substrates involved in zolpidem-mediated sleep. We also investigated the role of synaptic-inhibition onto corticothalamic-neurons in anaesthetic-induced LOC and sleep-wake. To do this, we genetically ablated 2-subunits from layer-6 corticothalamic-cells by crossing Ntsr1-Cre mice with GABAA-2I77lox mice. We found this reduced isoflurane sensitivity, but left sleep-wake behaviours virtually unaffected.Open Acces