J Neurosci

Global hypoxia-ischemia interrupts oxygen delivery and blood flow to the entire brain. Previous studies of global brain hypoxia-ischemia have primarily focused on injury to the cerebral cortex and to the hippocampus. Susceptible neuronal populations also include inhibitory neurons in the thalamic reticular nucleus. We therefore investigated the impact of global brain hypoxia-ischemia on the thalamic circuit function in the somatosensory system of young rats. We used single neuron recordings and controlled whisker deflections to examine responses of thalamocortical neurons to sensory stimulation in rat survivors of 9 min of asphyxial cardiac arrest incurred on postnatal day 17. We found that 48-72 h after cardiac arrest, thalamocortical neurons demonstrate significantly elevated firing rates both during spontaneous activity and in response to whisker deflections. The elevated evoked firing rates persist for at least 6-8 weeks after injury. Despite the overall increase in firing, by 6 weeks, thalamocortical neurons display degraded receptive fields, with decreased responses to adjacent whiskers. Nine minutes of asphyxial cardiac arrest was associated with extensive degeneration of neurites in the somatosensory nucleus as well as activation of microglia in the reticular nucleus. Global brain hypoxia-ischemia during cardiac arrest has a long-term impact on processing and transfer of sensory information by thalamic circuitry. Thalamic circuitry and normalization of its function may represent a distinct therapeutic target after cardiac arrest.5K12-HD047349-08/HD/NICHD NIH HHS/United StatesK12 HD001487/HD/NICHD NIH HHS/United StatesK12 HD001487-15/HD/NICHD NIH HHS/United StatesK12 HD047349/HD/NICHD NIH HHS/United StatesK12 HD047349-09/HD/NICHD NIH HHS/United StatesK12-HD01487/HD/NICHD NIH HHS/United StatesND045968/ND/ONDIEH CDC HHS/United StatesNS07003/NS/NINDS NIH HHS/United StatesNS19950/NS/NINDS NIH HHS/United StatesNS30318/NS/NINDS NIH HHS/United StatesR01 HD045968/HD/NICHD NIH HHS/United StatesR01 HD045968-05/HD/NICHD NIH HHS/United StatesR01 NS019950/NS/NINDS NIH HHS/United StatesR01 NS019950-28/NS/NINDS NIH HHS/United StatesR21 NS070003/NS/NINDS NIH HHS/United StatesR21 NS070003-01/NS/NINDS NIH HHS/United States2012-10-04T00:00:00Z22492052PMC335078

Cardiac arrest-induced global brain hypoxia-ischemia during development affects spontaneous activity organization in rat sensory and motor thalamocortical circuits during adulthood

Normal maturation of sensory information processing in the cortex requires patterned synaptic activity during developmentally regulated critical periods. During early development, spontaneous synaptic activity establishes required patterns of synaptic input, and during later development it influences patterns of sensory experience-dependent neuronal firing. Thalamocortical neurons occupy a critical position in regulating the flow of patterned sensory information from the periphery to the cortex. Abnormal thalamocortical inputs may permanently affect the organization and function of cortical neuronal circuits, especially if they occur during a critical developmental window. We examined the effect of cardiac arrest (CA)-associated global brain hypoxia-ischemia in developing rats on spontaneous and evoked firing of somatosensory thalamocortical neurons and on large-scale correlations in the motor thalamocortical circuit. The mean spontaneous and sensory-evoked firing rate activity and variability were higher in CA injured rats. Furthermore, spontaneous and sensory-evoked activity and variability were correlated in uninjured rats, but not correlated in neurons from CA rats. Abnormal activity patterns of ventroposterior medial nucleus (VPm) neurons persisted into adulthood. Additionally, we found that neurons in the entopeduncular nucleus (EPN) in the basal ganglia had lower firing rates yet had higher variability and higher levels of burst firing after injury. Correlated levels of power in local field potentials (LFPs) between the EPN and the motor cortex (MCx) were also disrupted by injury. Our findings indicate that hypoxic-ischemic injury during development leads to abnormal spontaneous and sensory stimulus-evoked input patterns from thalamus to cortex. Abnormal thalamic inputs likely permanently and detrimentally affect the organization of cortical circuitry and processing of sensory information. Hypoxic-ischemic injury also leads to abnormal single neuron and population level activity in the basal ganglia that may contribute to motor dysfunction after injury. Combination of deficits in sensory and motor thalamocortical circuit function may negatively impact sensorimotor integration in CA survivors. Modulation of abnormal activity patterns post-injury may represent a novel therapeutic target to improve neurologic function in survivors

Electrophysiological Brain Monitoring after Cardiac Arrest with Temperature Management

Cardiac arrest (CA) is the leading cause of disability and death annually in the United States. Therapeutic hypothermia (TH) has been recommended as one of the standard practices for improving neurological outcome and survival to treat out-of-hospital CA patients after resuscitation. However, many clinical prognostic markers after resuscitation for predicting outcome have been less reliable under hypothermia. Therefore, there is a strong need to evaluate the prognostic value of current prognostic markers for hypoxic-ischemic brain injury after CA. The first part of this work was to review current literature and assess the prognostic value of current significant breakthroughs in neurophysiologic and electrophysiological methods for CA patients treated with TH in order to provide a comprehensive frame for future work. Due to the restrictions of standard clinical examinations and neuroimaging techniques in detecting brain injury, electroencephalography (EEG) has emerged as one of the commonly used bed-side real-time monitoring tools for prognostication. Instead of the subjective and impractical analysis of waveform-based raw EEG signals, we applied two quantitative methods – information quantity (IQ) and sub-band IQ (SIQ) – to quantify and examine the accuracy of prognostic value of EEG markers on predicting recovery under TH in the second part of this work. Our study discovered that both IQ and SIQ accurately predict neurologic outcome at the early stage of cerebral recovery. Moreover, high-frequency oscillations (HFO) were particularly noticeable during the recovery from severe brain injury indicated by IQ, and SIQ was able to provide additional standard clinical EEG bands of interests. The ischemic brain after CA is sensitive to trivial fluctuations of temperature. Previously, we only observed temperature management strongly affects the recovery of global EEG. However, EEG signals can be decomposed into different frequency sub-bands in clinical practices, which are related to different brain functions, and the association has not been elucidated between the recovery of each sub-band EEG and temperature management. In the third part of this work, we employed SIQ, of which indicative ability has been proven in the last part, to determine the most relevant sub-bands of EEG during brain recovery with temperature manipulation. It was found for the first time that gamma-band EEG activity, linked with high cognitive processes, was primarily affected by temperature and strongly associated with neurologic outcome, while delta-band played a role as constant component of EEG without stable relationship with temperature or outcome. Somatosensory evoked potentials (SSEPs), especially N20 responses in human, are able to evaluate the somatosensory system functioning, which are also regarded as a reliable early prognostic marker for post-CA neurologic outcome. Transcranial direct current stimulation (tDCS) is a non-invasive technique to modulate the cerebral excitability and activity which has been confirmed by motor evoked potentials (MEPs), but it is still unclear whether it can affect the somatosensory cortex. The final part of this work preliminarily studied the alternations of excitability of somatosensory cortex by tDCS and investigated the potential of SSEPs on measuring the after-effect of tDCS

Evoked Potentials and Their Applications in Cardiac Arrest, Prosthetic Feedback, and Focused Ultrasound

The hypoxic-ischemic (HI) brain injury is a major complication after cardiac arrest (CA). While the HI brain injury affects all regions of the brain, the majority of the studies have focused on the injury of the cerebral cortex and the hippocampus. The thalamus is an important subcortical structure due to its functions in sensation, sleep, attention, and arousal, and has been shown to be selectively vulnerable to HI injury. Despite the importance of the thalamus, there does not exists a translatable quantitative metric of thalamic injury after CA. Thus, this thesis focuses on studying thalamic injury after CA using somatosensory evoked potentials (SSEPs). The thesis first reviews past studies on thalamic blood flow, metabolism, immune response, cell damage, and electrophysiology change after CA to paint a full picture of the problem. The existing quantitative metrics of somatosensory evoked potentials to evaluate the integrity of the somatosensory pathway after CA are then reported to identify potential areas for breakthrough. Lastly, our current work on noninvasive monitoring of thalamocortical (TC) connectivity with wavelet filtering and Granger causality (GC) analysis is presented. Multiresolution wavelet (MRW) analysis extracted the SSEP N10 and high-frequency oscillation (HFO) components. The Granger causality between the two components were calculated. The results show that the HFO to N10 GC measure could reflect the severity of CA and highlights the first 10 minutes post-return of spontaneous circulation (ROSC) as the critical period for TC dissociation intervention. In the last two parts of the thesis, additional projects utilizing evoked potentials to study the ultrasound neuromodulation effect on the spinal cord and the cognitive limitations of prosthetic sensory feedback were also reported. These works are documented for archiving purposes and enlightening readers on the broad spectrum of evoked potential applications. Motor evoked potential amplitudes were suppressed during low-frequency focused ultrasound (LIFUS) modulation and gradually recovered after modulation. The future goal of this project is to use focused ultrasound to inhibit TC neurons and to increase TC association in the acute phase of recovery after cardiac arrest. P300 event-related potential is commonly associated with the subject's level of confidence about the category of a stimulus. When a new sensory feedback intensity was introduced, no different in force level was found, but the higher P300 amplitude in response to the novel sensory stimulation showed that the brain were able to recognize the new stimulation level. This work provides evidence that the upper limit of prosthetic sensory feedback level should be more than just three levels

When is “brainstem death” brain death? The case for ancillary testing in primary infratentorial brain lesion

peer reviewedThe widely accepted concept of brain death (BD) comprises the demonstration of irreversible coma in combination with the loss of brainstem reflexes and irreversible apnea. In some countries the combined clinical finding of coma, apnea, and loss of all tested brainstem reflexes (“brainstem death”) is sufficient for diagnosing BD irrespective of the primary location of brain lesion. The present article aims to substantiate the need for ancillary testing in patients with primary infratentorial brain lesions. Anatomically, the “brainstem-death” syndrome can theoretically occur without relevant lesion of the mesopontine tegmental reticular formation (MPT-RF). Thus, a brainstem lesion may cause an apneic total locked-in syndrome, a rare syndrome with preserved capability for consciousness, mimicking “brainstem death”. Findings in animals and humans have shown that alpha- or alpha/theta- EEG patterns in case of isolated brainstem lesion indicate intactness of relevant parts of the MPT-RF. In such patients the presence of irreversible coma has to be doubted, and the potential capacity for some degree of consciousness cannot be excluded as long as the EEG activity persists. Consequently the demonstration of either ancillary finding, electro-cortical inactivity or, preferably, cerebral circulatory arrest, is mandatory for diagnosing BD in patients with a primary infratentorial brain lesion

Incessant transitions between active and silent states in cortico-thalamic circuits and altered neuronal excitability lead to epilepsy

La ligne directrice de nos expériences a été l'hypothèse que l'apparition et/ou la persistance des fluctuations de longue durée entre les états silencieux et actifs dans les réseaux néocorticaux et une excitabilité neuronale modifiée sont les facteurs principaux de l'épileptogenèse, menant aux crises d’épilepsie avec expression comportementale. Nous avons testé cette hypothèse dans deux modèles expérimentaux différents. La déafférentation corticale chronique a essayé de répliquer la déafférentation physiologique du neocortex observée pendant le sommeil à ondes lentes. Dans ces conditions, caractérisées par une diminution de la pression synaptique et par une incidence augmentée de périodes silencieuses dans le système cortico-thalamique, le processus de plasticité homéostatique augmente l’excitabilité neuronale. Par conséquent, le cortex a oscillé entre des périodes actives et silencieuses et, également, a développé des activités hyper-synchrones, s'étendant de l’hyperexcitabilité cellulaire à l'épileptogenèse focale et à des crises épileptiques généralisées. Le modèle de stimulation sous-liminale chronique (« kindling ») du cortex cérébral a été employé afin d'imposer au réseau cortical une charge synaptique supérieure à celle existante pendant les états actifs naturels - état de veille ou sommeil paradoxal (REM). Dans ces conditions un mécanisme différent de plasticité qui s’est exprimé dans le système thalamo-corticale a imposé pour des longues périodes de temps des oscillations continuelles entre les époques actives et silencieuses, que nous avons appelées des activités paroxysmiques persistantes. Indépendamment du mécanisme sous-jacent de l'épileptogenèse les crises d’épilepsie ont montré certaines caractéristiques similaires : une altération dans l’excitabilité neuronale mise en évidence par une incidence accrue des décharges neuronales de type bouffée, une tendance constante vers la généralisation, une propagation de plus en plus rapide, une synchronie augmentée au cours du temps, et une modulation par les états de vigilance (facilitation pendant le sommeil à ondes lentes et barrage pendant le sommeil REM). Les états silencieux, hyper-polarisés, de neurones corticaux favorisent l'apparition des bouffées de potentiels d’action en réponse aux événements synaptiques, et l'influence post-synaptique d'une bouffée de potentiels d’action est beaucoup plus importante par rapport à l’impacte d’un seul potentiel d’action. Nous avons également apporté des évidences que les neurones néocorticaux de type FRB sont capables à répondre avec des bouffées de potentiels d’action pendant les phases hyper-polarisées de l'oscillation lente, propriété qui peut jouer un rôle très important dans l’analyse de l’information dans le cerveau normal et dans l'épileptogenèse. Finalement, nous avons rapporté un troisième mécanisme de plasticité dans les réseaux corticaux après les crises d’épilepsie - une diminution d’amplitude des potentiels post-synaptiques excitatrices évoquées par la stimulation corticale après les crises - qui peut être un des facteurs responsables des déficits comportementaux observés chez les patients épileptiques. Nous concluons que la transition incessante entre des états actifs et silencieux dans les circuits cortico-thalamiques induits par disfacilitation (sommeil à ondes lentes), déafférentation corticale (épisodes ictales à 4-Hz) ou par une stimulation sous-liminale chronique (activités paroxysmiques persistantes) crée des circonstances favorables pour le développement de l'épileptogenèse. En plus, l'augmentation de l’incidence des bouffées de potentiels d’actions induisant une excitation post-synaptique anormalement forte, change l'équilibre entre l'excitation et l'inhibition vers une supra-excitation menant a l’apparition des crises d’épilepsie.The guiding line in our experiments was the hypothesis that the occurrence and / or the persistence of long-lasting fluctuations between silent and active states in the neocortical networks, together with a modified neuronal excitability are the key factors of epileptogenesis, leading to behavioral seizures. We addressed this hypothesis in two different experimental models. The chronic cortical deafferentation replicated the physiological deafferentation of the neocortex observed during slow-wave sleep (SWS). Under these conditions of decreased synaptic input and increased incidence of silent periods in the corticothalamic system the process of homeostatic plasticity up-regulated cortical cellular and network mechanisms and leaded to an increased excitability. Therefore, the deafferented cortex was able to oscillate between active and silent epochs for long periods of time and, furthermore, to develop highly synchronized activities, ranging from cellular hyperexcitability to focal epileptogenesis and generalized seizures. The kindling model was used in order to impose to the cortical network a synaptic drive superior to the one naturally occurring during the active states - wake or rapid eye movements (REM) sleep. Under these conditions a different plasticity mechanism occurring in the thalamo-cortical system imposed long-lasting oscillatory pattern between active and silent epochs, which we called outlasting activities. Independently of the mechanism of epileptogenesis seizures showed some analogous characteristics: alteration of the neuronal firing pattern with increased bursts probability, a constant tendency toward generalization, faster propagation and increased synchrony over the time, and modulation by the state of vigilance (overt during SWS and completely abolished during REM sleep). Silent, hyperpolarized, states of cortical neurons favor the induction of burst firing in response to depolarizing inputs, and the postsynaptic influence of a burst is much stronger as compared to a single spike. Furthermore, we brought evidences that a particular type of neocortical neurons - fast rhythmic bursting (FRB) class - is capable to consistently respond with bursts during the hyperpolarized phase of the slow oscillation, fact that may play a very important role in both normal brain processing and in epileptogenesis. Finally, we reported a third plastic mechanism in the cortical network following seizures - a decreasing amplitude of cortically evoked excitatory post-synaptic potentials (EPSP) following seizures - which may be one of the factors responsible for the behavioral deficits observed in patients with epilepsy. We conclude that incessant transitions between active and silent states in cortico-thalamic circuits induced either by disfacilitation (sleep), cortical deafferentation (4-Hz ictal episodes) and by kindling (outlasting activities) create favorable circumstances for epileptogenesis. The increase in burst-firing, which further induce abnormally strong postsynaptic excitation, shifts the balance of excitation and inhibition toward overexcitation leading to the onset of seizures

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

Neuropathology in the dorsolateral prefrontal cortex in Parkinson's disease

Thesis (Ph.D.)--Boston UniversityDegeneration of dopaminergic neurons in the substantia nigra pars compacta is the hallmark neuropathological feature of Parkinson's disease (PD). Multiple lines of evidence from anatomical and imaging studies indicate that cell loss or cell dysfunction also occur in other brain regions. The dorsolateral prefrontal cortex (DLPFC) is a region of interest because it could be implicated in both cognitive and motor symptoms of PD. However, studies in this brain region are limited and the extent of pathology is unclear. Work in this thesis was aimed at identifying possible neuropathology in post-mortem PD tissue from Brodmann area 9 (BA9), a region of the DLPFC. In the first study, using design-based stereology and radioisotopic in situ hybridization histochemistry (ISHH), we found that expression of two mitochondrial genes, NDUFS1 and COX1, was not altered and that no global loss of neurons occurs in BA9 in PD. In a second study, using ISHH and gene expression microarray analysis (One-Color Agilent 60-mer Whole Human Genome Microarray), we found decreased gene expression of the GABA-synthesizing enzyme glutamic acid decarboxylase (GAD67) in BA9 in PD, an effect that was not paralleled by a decrease in the numbers of GAD67 mRNA-expressing neurons. In a third study, using ISHH, we found that gene expression of the calcium-binding protein parvalbumin, which is selectively expressed in a subset of cortical GABAergic interneurons, is decreased in BA9 in PD. However, we found no loss of immunolabeled parvalbumin-positive neurons in BA9 in PD. In summary, the results indicate that expression of two key markers of GABAergic activity, GAD67 and parvalbumin, is depressed in BA9 in PD and that these effects are not due to a loss of neurons. This suggests that GABAergic neurotransmission is deficient in the DLPFC in PD and we propose that treatments aimed at restoring GABAergic inhibition in BA9 would have therapeutic efficacy in the symptomatic treatment of PD