A transient cortical state with sleep-like sensory responses precedes emergence from general anesthesia in humans

During awake consciousness, the brain intrinsically maintains a dynamical state in which it can coordinate complex responses to sensory input. How the brain reaches this state spontaneously is not known. General anesthesia provides a unique opportunity to examine how the human brain recovers its functional capabilities after profound unconsciousness. We used intracranial electrocorticography and scalp EEG in humans to track neural dynamics during emergence from propofol general anesthesia. We identify a distinct transient brain state that occurs immediately prior to recovery of behavioral responsiveness. This state is characterized by large, spatially distributed, slow sensory-evoked potentials that resemble the K-complexes that are hallmarks of stage two sleep. However, the ongoing spontaneous dynamics in this transitional state differ from sleep. These results identify an asymmetry in the neurophysiology of induction and emergence, as the emerging brain can enter a state with a sleep-like sensory blockade before regaining responsivity to arousing stimuli.National Institutes of Health (U.S.) (Grant K99-MH111748)National Institutes of Health (U.S.) (Grant R00-NS080911)National Institutes of Health (U.S.) (Grant DP2-OD006454)National Institutes of Health (U.S.) (Grant S10-RR023401)National Institutes of Health (U.S.) (Grant R01- NS062092)National Institutes of Health (U.S.) (Grant R01AG056015)National Institutes of Health (U.S.) (Grant P01GM118269)National Institutes of Health (U.S.) (Grant R01-EB009282

The Characterization Of Visual Evoked Feedforward-Feedback Travelling Waves In Mice During Waking And Anesthetized States

A cardinal feature of consciousness is the maintenance of a stable perceptual world. To accomplish this, sensory information must be faithfully relayed and integrated within the brain. General anesthetic agents reliably and reversibly produce states of unconsciousness. However, despite their ubiquitous use in medicine and science, the mechanisms by which anesthetics induce loss of consciousness remains unknown. Over the past 170 years, researchers have searched for the universal targets that anesthetic agents use to ablate perception (Alkire et al., 2008; Kelz and Mashour, 2019). However, there is not yet a common structural motif, receptor target, or sleep/arousal circuit that all known anesthetics interact with (Alkire et al., 2008; Kelz and Mashour, 2019). It was once postulated that anesthetics may ablate perception by disconnecting the cortex from incoming thalamic signals (Alkire et al., 2000; Alkire and Miller, 2005; White and Alkire, 2003); yet under anesthesia, neurons within primary cortical areas are still able to encode features of sensory stimuli, thereby suggesting sensory information is effectively relayed to the cortex (Hubel and Wiesel, 1962). Thus, it has been recently theorized that anesthetics may hinder the ability for sensory responses to faithfully participate in hierarchal, feedback and integrative circuits at a network level (Lee et al., 2009; Mashour, 2006, 2014). In this dissertation, I investigate this theory by analyzing the spatiotemporal features of visual evoked oscillations over multiple hierarchical cortical areas in awake and anesthetized mice presented with simple visual stimuli and answering a series of motivating questions. Are there consistent neurophysiological substrates to coordinate visual evoked activity across the many cortical regions involved in visual processing in awake mice, who have the ability to perceive stimuli? If so, what is the spatiotemporal structure of this activity pattern, and does it coordinate neural firing in disparate cortical areas? Can we identify patterns that may be related to hierarchical visual processing vs feedback signaling? How do mechanistically distinct anesthetic agents disrupt visual evoked patterns seen in the awake brain? Are there agent specific effects? And finally, can we identify a common mechanism by which all tested anesthetic agents breakdown visual evoked activity? While my research does not test perception per se, findings herein will provide the neurophysiological basis for the integration of visual-evoked activity across cortices during wakefulness, and the breakdown of this coordinated pattern of activity during anesthetic induced states of unconsciousness

Quantum information theoretic approach to the mind–brain problem

The brain is composed of electrically excitable neuronal networks regulated by the activity of voltage-gated ion channels. Further portraying the molecular composition of the brain, however, will not reveal anything remotely reminiscent of a feeling, a sensation or a conscious experience. In classical physics, addressing the mind–brain problem is a formidable task because no physical mechanism is able to explain how the brain generates the unobservable, inner psychological world of conscious experiences and how in turn those conscious experiences steer the underlying brain processes toward desired behavior. Yet, this setback does not establish that consciousness is non-physical. Modern quantum physics affirms the interplay between two types of physical entities in Hilbert space: unobservable quantum states, which are vectors describing what exists in the physical world, and quantum observables, which are operators describing what can be observed in quantum measurements. Quantum no-go theorems further provide a framework for studying quantum brain dynamics, which has to be governed by a physically admissible Hamiltonian. Comprising consciousness of unobservable quantum information integrated in quantum brain states explains the origin of the inner privacy of conscious experiences and revisits the dynamic timescale of conscious processes to picosecond conformational transitions of neural biomolecules. The observable brain is then an objective construction created from classical bits of information, which are bound by Holevo’s theorem, and obtained through the measurement of quantum brain observables. Thus, quantum information theory clarifies the distinction between the unobservable mind and the observable brain, and supports a solid physical foundation for consciousness research

State-Dependent Cortical Network Dynamics

Neuropsychiatric illness represents a major health burden in the United States with a paucity of effective treatment. Many neuropsychiatric illnesses are network disorders, exhibiting aberrant organization of coordinated activity within and between brain areas. Cortical oscillations, arising from the synchronized activity of groups of neurons, are important in mediating both local and long-range communication in the brain and are particularly affected in neuropsychiatric diseases. A promising treatment approach for such network disorders entails ‘correcting’ abnormal oscillatory activity through non-invasive brain stimulation. However, we lack a clear understanding of the functional role of oscillatory activity in both health and disease. Thus, basic science and translational work is needed to elucidate the role of oscillatory activity and other network dynamics in neuronal processing and behavior. Organized activity in the brain occurs at many spatial and temporal scales, ranging from the millisecond duration of individual action potentials to the daily circadian rhythm. The studies comprising this dissertation focused on organization in cortex at the time scale of milliseconds, assessing local field potential and spiking activity, and contribute to understanding (1) the effects of non-invasive brain stimulation on behavioral responses, (2) network dynamics within and across cortical areas during different states, and (3) how oscillatory activity organizes spiking activity locally and long-range during sustained attention. Taken together, this work provides insight into the physiological organization of network dynamics and can provide the basis for future rational design of non-invasive brain stimulation treatments.Doctor of Philosoph

Idiopaattinen epilepsia suomenpystykorvilla : Epidemiologinen, kliininen ja diagnostinen näkökulma

Epilepsy, a common neurologic disorder in dogs, has also been recognized in the Finnish Spitz dog (FSD) since the 1980s, but scientifically verified data has been lacking. In this thesis, epilepsy in FSDs was characterized. Diagnostic investigations, using tools such as magnetic resonance imaging (MRI) and electroencephalography (EEG), have not been used consistently in veterinary medicine to diagnose epilepsy in dogs. The usefulness of these modalities to diagnose different forms of canine epilepsy needs to be proven. Thus, FSDs with and without focal epilepsy were studied by MRI and EEG. In addition, the novel functional method to investigate epileptic dogs, 2-deoxy-2-[18F]fluoro-D-glucose (FDG) positron emission tomography (PET), was described and results were compared with EEG. Epidemiological information was based on 2141 FSDs, of which 143 were epileptic, and prevalence on 2069 living FSDs, of which 111 had epilepsy. The prevalence of idiopathic epilepsy (IE) in FSDs was found to be 5.3%; males were more predisposed to epilepsy. The median age at seizure onset was 3 years, seizure frequency was 3 per year, and duration of seizure episode was 12 min. Focal onset seizures, characterized by frequent behavioral and autonomic signs were the main phenotype of epilepsy in FSDs. Although epilepsy in FSDs follows a generally benign course, generalization of seizure indicate a progressive course of epilepsy. The heritability estimate of IE in FSDs (0.22) was best explained by polygenic traits. Although characterized with focal seizures, FSDs have non-lesional epilepsy based on 1.5T MRI examinations. Infrequent reversible brain changes can be found, as a consequence of seizures. Visual evaluation of EEG in epileptic FSDs showed interictal epileptiform paroxysmal activity (20%) less frequently than had been described previously. This activity was expressed by spikes, polyspikes, and spike slow-wave complexes in the posterior-occipital derivation. Epileptiform activity, consisting of midline spikes, was recognized in healthy FSDs. Sleep transients, which were frequently found in FSDs from both groups, could be easily misinterpreted as epileptiform activity. Quantitative EEG showed significant difference in various frequency bands related to diseased status or medication. Cerebral glucose utilization was examined by FDG-PET in 11 epileptic and 8 healthy FSDs. Glucose uptake abnormalities/asymmetries were detected in various brain regions of 82% of epileptic and in 50% of control FSDs; findings in the occipital cortex specifically associated with epilepsy. The epileptic dogs had significantly lower standardized uptake values in numerous cortical regions, cerebellum, and hippocampus compared to the control dogs. The low cortical glucose uptake values found in the occipital lobe in both groups of FSDs is an unique finding and may indirectly reflect the lowered seizure threshold in that region characteristic for this dog breed. Inability to reveal significant difference of white matter normalized uptake values and left-right asymmetry indexes between epileptic and control groups might be related to the method used to define regions of interest. Based on these results, epilepsy in FSDs is defined as idiopathic epilepsy, as FSDs lack changes on the brain MRI and epilepsy is genetically determined. EEG and FDG-PET suggest involvement of the occipital region, although also wider posterior cortical areas could be related to epileptogenesis in FSDs. Visual evaluation of both EEG and FDG-PET can support the diagnosis of IE in dogs. Although diagnostic yield of EEG to diagnose epilepsy seems to be lower than suggested for dogs, it is a method of choice for everyday clinical settings. FDG-PET is a useful research modality for examining epileptic dogs, where visual detection of hypometabolic areas provides the highest sensitivity. Quantitative assessment methods of EEG and FDG-PET can be beneficial, but should be used alongside visual evaluation in epileptic dogs.Epilepsia on yleinen neurologinen sairaus koirilla. Sitä on tavattu suomenpystykorvilla jo 1980-luvulta lähtien, mutta tieteellisesti varmennettua tietoa ei ole aiemmin ollut saatavilla kyseisen rodun epilepsiasta. Tässä väitöskirjassa kuvataan suomenpystykorvien epilepsian esiintyvyyttä, kliinisia oireita ja diagnostiikka. Koiria tutkitiin magneettikuvauksen (MRI) ja aivosähkökäyrätutkimuksen (EEG) avulla. Uutena toiminnallisen-kuvantamisen menetelmänä koirien epilepsian tutkimisissa käytetiin positroniemissiotomografia (PET). ----- Epidemiologinen tieto perustui 2141 suomenpystykorvan tietoihin ja esiintyvyys 2069 elossa olevan Suomenpystykorvan tietoihin. Epilepsian esiintyvyys suomenpystykorvilla todettiin olevan 5,3% urosten ollessa alttiimpia sairastumaan epilepsiaan. Kohtaukset alkavat pystykorvilla keskimäärin 3 vuoden iässä, niitä on keskimäärin kolmesti vuodessa, ja kohtauksen tyypillinen kesto on 12 minuuttia. Rodulle tyypillisiä olivat paikallisalkuiset kohtaukset, joihin liittyi tavallisesti käytösmuutoksia ja autonomisia oireita, kuten oksentelua ja kuolaamista. Kohtausten yleistyminen voi viitata epilepsian etenemiseen, vaikka pystykorvien epilepsian kulku on yleensä hyvänlaatuinen. Suomenpystykorvien idiopaattisen epilepsian perinnöllisyysasteen arvio (0.22) selittyy parhaiten usean geenin mallin avulla. Vaikkakin suomenpystykorvien epilepsialle tyypillisiä ovat paikalliset kohtaukset, korkeakenttämagneetilla tehtyjen tutkimuksien perusteella kyseessä on epilepsia, jossa ei havaita aivoissa rakenteellisia muutoksia. Harvakseltaan voidaan kuitenkin havaita palautuvia, kohtausten seurauksena syntyneitä muutoksia aivoissa. Epilepsiaa sairastavien suomenpystykorvien aivosähkökäyrässä havaittiin kohtausten välillä epileptistä aktiivisuutta harvemmin (20%) kuin on raportoitu aiemmin. Tietyntyyppistä epänormaalia aktiivisuutta havaittiin myös terveillä pystykorvilla, mutta löydöksen kliininen merkitys on tuntematon. Uneen liittyvää aktiivisuutta, joka voidaan helposti tulkita virheellisesti epileptiseksi aktiivisuudeksi, todettiin sekä terveillä että sairailla koirilla. Aivosähkökäyrän kvantitatiivisessa tulkinnassa havaittiin merkittäviä eroja riippuen terveysstatuksesta tai lääkityksestä. ------ Aivojen glukoosinkäyttöä tutkittiin 2-deoksi-2-[18F]fluoro-D-glukoosi (FDG)-PET avulla 11 epileptisellä ja 8 terveellä suomenpystykorvalla. Glukoosinkäytössä todettiin epänormaaliutta tai epäsymmetrisyyttä eri aivoalueilla 82%:lla epileptisistä ja 50%:lla terveistä koirista; muutokset erityisesti isoaivojen takaraivonlohkon kuorikerroksen alueella liittyivät epilepsiaan. Epileptisillä koirilla todettiin merkittävästi alhaisemmat glukoosinkäyttöarvot useilla aivoalueilla verrattuna kontrollikoiriin. Isoaivojen kuorikerroksen takaraivonlohkon alhaiset glukoosinkäyttöarvot molemmissa koiraryhmissä ovat aiemmin havaitsematon löydös ja tämä saattaa epäsuorasti viitata alentuneeseen kohtauskynnykseen kyseisellä alueella luonteenomaisena tutkitulle rodulle. Kyvyttömyys havaita merkittäviä eroja epileptisten ja kontrolliryhmien välillä valkeaan ainekseen suhteutetuissa glukoosinkäyttöarvoissa ja vasen-oikea epäsymmetria-indekseissä voi liittyä käytettyihin menetelmiin. Näihin tuloksiin perustuen suomenpystykorvien epilepsia luokitellaan idiopaattiseksi epilepsiaksi, koska aivojen magneettikuvauksessa ei havaita muutoksia ja epilepsia on perinnöllinen kyseessä olevalla rodulla. EEG ja FDG-PET viittaavat takaraivonlohkon osallisuuteen, vaikkakin myös laajempi taaimmaisten aivoalueiden mukanaolo on mahdollinen pystykorvien epilepsian synnyssä. EEG ja FDG-PET visuaalinen analyysi voivat tukea idiopaattisen epilepsian diagnoosin tekemistä koirilla. Vaikkakin EEG:n tuoma diagnostinen apu koirilla näyttää olevan alhaisempi kuin aiemmin on ehdotettu, se on ensisijainen menetelmä jokapäiväisessä kliinisessä työssä. FDG-PET on hyödyllinen menetelmä tutkimusmielessä arvioitaessa epileptisiä koiria, ja siinä hypometabolisten alueiden visuaalinen havaitseminen antaa parhaimman herkkyyden. EEG ja FDG-PET tulosten kvantitatiivinen arviointi voi olla hyödyllistä, mutta niitä tulisi käyttää rinnakkain visuaalisen analyysin kanssa

Fluctuations of attention network activation during the resting state reflect fluctuations in subjective attentional state.

peer reviewe

Mécanismes cérébraux de la régulation de la douleur : perception de la douleur et hypoalgésie induite psychologiquement

Objectif : Cette thèse a pour but de préciser les mécanismes neuropsychologiques de la douleur, de la régulation endogène de la douleur et de l'hypoalgésie induite psychologiquement (HIP) par la synthèse de près de trente ans de recherche imagerie cérébrale fonctionnelle. Méthodologie : Étant donné l'abondance des études sur le sujet et le manque d'intégration de leurs résultats, la technique de métaanalyse quantitative basée sur les coordonnées d'activation cérébrale fut privilégiée dans cette thèse, telle qu’implémentée dans l'algorithme ALE (Activation Likelyhood Estimate). Une force supplémentaire de cette thèse repose sur la rigueur du processus de sélection des articles. En effet, les études incluses dans les métaanalyses devaient satisfaire des critères stricts d'inclusion, ceci dans le but de favoriser la précision et la validité des conclusions subséquentes. Étude 1 : Le premier article visait à identifier les aires cérébrales impliquées dans la réduction de la douleur par des méthodes psychologiques d'interventions. Les articles retenus portent sur une variété de méthodes d'intervention, telles que le placebo, l'hypnose, la méditation, la perception de contrôle sur la stimulation douloureuse et l'induction d'émotions. Les résultats indiquent que l'HIP implique un vaste réseau d'activation qui comprend le cortex cingulaire antérieur, l'insula antérieure, les zones orbitofrontale et préfrontale latérale, ainsi que les régions pariétale, temporale et souscorticales. Ces activations reflèteraient l'implication des mécanismes neuropsychologiques cognitifs et émotionnels sous-tendent les interventions psychologiques ciblées par ces études, incluant la conscience de soi et la motivation. De plus, les divergences de patron d'activation entre les approches ont été explorées, notamment pour le placebo et la distraction. Étude 2 : Le deuxième article a identifié des patrons d'activations préférentiellement associés à la perception de la douleur, à l'HIP, ainsi que des activations communément associées à la douleur et l'HIP. Les résultats indiquent que 1) la perception de la douleur est associée à l'activation d'aires somatosensorielles et motrices, ce qui pourrait être le reflet de la préparation d'une action adaptative, 2) l'HIP est liée à l'engagement de régions préfrontales antéromédianes et orbitales, possiblement en lien avec des processus motivationnels et émotionnels, et 3) la douleur et l'HIP sont associés à l'activation d'aires préfrontales dorsolatérales, de l'insula antérieure et du cortex cingulaire moyen, ce qui pourrait refléter l'engagement spontané pendant la douleur de mécanismes endogènes de régulation descendante. Conclusion : Par ces études, cette thèse fait le point sur les mécanismes cérébraux impliqués différentiellement dans la perception de la douleur, dans sa régulation endogène et dans l'hypoalgésie induite psychologiquement.Objective: This thesis aims to clarify the neuropsychological mechanisms of pain, of the endogenous regulation of pain and of psychologically induced hypoalgesia (PIH), through the synthesis of almost thirty years of functional brain imaging research. Methodology: Given the abundance of studies in this domain and the lack of integration of their results, we used the quantitative meta-analysis technique based on brain activation using the ALE (Activation likelihood Estimate) statistic. The strength of this thesis lies in the globalized perspective of the litterature, and in the rigor of the article selection process from which results were extracted. Indeed, the studies included in the meta-analyses needed to meet strict inclusion criteria in order to strengthen the accuracy and the validity of subsequent conclusions. Study 1: The first article is aimed at identifying brain areas involved in pain reduction through psychological methods of intervention. Chosen articles that covered a variety of approaches, such as placebo, hypnosis, meditation, perception of control over the stimulation, and induction of emotions. Analysis across these various studies indicated that PIH involves a broad network of activation that includes the anterior cingulate cortex, anterior insulae, orbital and lateral prefrontal and frontal areas, as well as parietal, temporal and subcortical regions. This activation network may reflect the involvement of diverse neuropsychological mechanisms in the various affective, self-awareness, cognitive and motivational processes underlying the psychological interventions targeted by these studies. In addition, we explored some specific patterns of brain activity related to placebo and distraction, in comparison to other approaches. We propose several hypotheses regarding the distinctive neuropsychological processes underlying these approaches. Study 2: The second article aimed at investigating patterns of brain activity preferentially associated with pain perception or with PIH. First we assessed patterns of increased and decreased activity during experimental pain in healthy volunteers. Second we determined the brain regions preferentially activated during pain perception or during PIH with subtraction analyses. Using a conjunction analysis, we also determined a set of brain regions possibly involved in regulatory processes activated spontaneously during acute of pain. Our results indicate that 1) somatosensory and motor areas are preferentially related to pain perception, which may reflect the preparation of a motor response, 2) dorsolateral prefrontal areas, anterior insula and the anterior midcingulate cortex were associated with both pain and PIH and may reflect the spontaneous activation of top-down regulation mechanisms during pain, and 3) antero-medial and orbital prefrontal regions were preferentially associated with PIH, which may indicate motivational and emotional processes associated with the engagement of an externally driven hypoalgesic procedure

Oscillatory activity in the basal ganglia - is it relevant to movement disorders therapy?

Chronic high frequency stimulation of the basal ganglia can be a highly effective intervention for movement disorders in patients. In the past decade, therapeutic benefits have been seen with stimulation of the subthalamic nucleus and globus pallidus interna for Parkinson's disease (PD) and dystonia, respectively. These procedures have allowed direct recording of basal ganglia activity and have suggested that abnormal synchronisation of neurons in these nuclei may contribute to motor impairment. This thesis explores the possible correlation between synchronised activity in the basal ganglia, as evidenced by oscillations in local field potentials, and movement disorders. In Chapter 3, we demonstrate the correlation between synchronization at frequencies under 10 Hz in the globus pallidus interna and dystonic EMG. This low frequency activity is shown to be locked to neuronal activity within GPi in patients with dystonia (Chapter 4). Deep brain stimulation is thought to suppress spontaneous pathological activity in the basal ganglia. Equally, however, it must also suppress any residual physiological activity in these nuclei. In Chapter 5, we demonstrate that the basal ganglia are involved in the processing of simple limb movements in the human, by separating the effects of deep brain stimulation on pathological and physiological activities based on baseline task performance. An impairment of motor performance was seen during high frequency stimulation in those patients with the best task performance at baseline. This deleterious effect, however, should be distinguished from the effect of direct stimulation at 20 Hz in Parkinson's disease. Oscillatory activity at around 20 Hz is thought to be a core feature in Parkinson's disease. In Chapter 6, we demonstrate that the excessive synchronization imposed by stimulation of the subthalamic nucleus at 20 Hz slows movement, in those patients with the best task performance at baseline. This supports the notion that synchronization around 20 Hz may be causally linked to bradykinesia. Last, the therapeutic effectiveness of DBS therapy for patients with PD partially relies on the accurate localisation of the motor region of the subthalamic nucleus. In Chapter 7, we propose an alternative method for the localization of this region using the spontaneous pathological 20 Hz activity to be found in this nucleus. The findings of these studies provide evidence that basal ganglia oscillatory activities of differing frequencies contribute to movement disorders