Optogenetic Activation of Afferent Pathways in Brain Slices and Modulation of Responses by Volatile Anesthetics

Anesthetics influence consciousness in part via their actions on thalamocortical circuits. However, the extent to which volatile anesthetics affect ...

University of Wisconsin

Technion - Israel Institute of Technology

Surgery in patients with Parkinson disease is associated with a high rate of complications largely because of difficulties in maintaining the antiparkinsonian treatment regimen perioperatively. The aim of the study was to investigate the safety and efficacy of intravenous administration of amantadine on parkinsonian features during and after surgery.

Safety of perioperative treatment with intravenous amantadine in patients with Parkinson disease.

Beta-band synchronous oscillations in the dorsolateral region of the subthalamic nucleus (STN) of human patients with Parkinson's disease (PD) have been frequently reported. However, the correlation between STN oscillations and synchronization has not been thoroughly explored. The simultaneous recordings of 2390 multi-unit pairs recorded by two parallel microelectrodes (separated by fixed distance of 2 mm, n = 72 trajectories with two electrode tracks >4 mm STN span) in 57 PD patients undergoing STN deep brain stimulation surgery were analyzed. Automatic procedures were utilized to divide the STN into dorsolateral oscillatory and ventromedial non-oscillatory regions, and to quantify the intensity of STN oscillations and synchronicity. Finally, the synchronicity of simultaneously vs. non-simultaneously recorded pairs were compared using a shuffling procedure. Synchronization was observed predominately in the beta range and only between multi-unit pairs in the dorsolateral oscillatory region (n = 615). In paired recordings between sites in the dorsolateral and ventromedial (n = 548) and ventromedial-ventromedial region pairs (n = 1227), no synchronization was observed. Oscillation and synchronicity intensity decline along the STN dorsolateral-ventromedial axis suggesting a fuzzy border between the STN regions. Synchronization strength was significantly correlated to the oscillation power, but synchronization was no longer observed following shuffling. We conclude that STN long-range beta oscillatory synchronization is due to increased neuronal coupling in the Parkinsonian brain and does not merely reflect the outcome of oscillations at similar frequency. The neural synchronization in the dorsolateral (probably the motor domain) STN probably augments the pathological changes in firing rate and patterns of subthalamic neurons in PD patients. 

Subthalamic nucleus long-range synchronization-an independent hallmark of human Parkinson's disease.

The state of the sensory cortical network can have a profound impact on neural responses and perception. In rodent auditory cortex, sensory responses are reported to occur in the context of network events, similar to brief UP states, that produce "packets" of spikes and are associated with synchronized synaptic input (Bathellier et al., 2012; Hromadka et al., 2013; Luczak et al., 2013). However, traditional models based on data from visual and somatosensory cortex predict that ascending sensory thalamocortical (TC) pathways sequentially activate cells in layers 4 (L4), L2/3, and L5. The relationship between these two spatio-temporal activity patterns is unclear. Here, we used calcium imaging and electrophysiological recordings in murine auditory TC brain slices to investigate the laminar response pattern to stimulation of TC afferents. We show that although monosynaptically driven spiking in response to TC afferents occurs, the vast majority of spikes fired following TC stimulation occurs during brief UP states and outside the context of the L4>L2/3>L5 activation sequence. Specifically, monosynaptic subthreshold TC responses with similar latencies were observed throughout layers 2-6, presumably via synapses onto dendritic processes located in L3 and L4. However, monosynaptic spiking was rare, and occurred primarily in L4 and L5 non-pyramidal cells. By contrast, during brief, TC-induced UP states, spiking was dense and occurred primarily in pyramidal cells. These network events always involved infragranular layers, whereas involvement of supragranular layers was variable. During UP states, spike latencies were comparable between infragranular and supragranular cells. These data are consistent with a model in which activation of auditory cortex, especially supragranular layers, depends on internally generated network events that represent a non-linear amplification process, are initiated by infragranular cells and tightly regulated by feed-forward inhibitory cells. 

Spiking in auditory cortex following thalamic stimulation is dominated by cortical network activity.

The mechanism of loss of consciousness (LOC) under anesthesia is unknown. Because consciousness depends on activity in the cortico-thalamic network, anesthetic actions on this network are likely critical for LOC. Competing theories stress the importance of anesthetic actions on bottom-up "core" thalamo-cortical (TC) vs. top-down cortico-cortical (CC) and matrix TC connections. We tested these models using laminar recordings in rat auditory cortex in vivo and murine brain slices. We selectively activated bottom-up vs. top-down afferent pathways using sensory stimuli in vivo and electrical stimulation in brain slices, and compared effects of isoflurane on responses evoked via the two pathways. Auditory stimuli in vivo and core TC afferent stimulation in brain slices evoked short latency current sinks in middle layers, consistent with activation of core TC afferents. By contrast, visual stimuli in vivo and stimulation of CC and matrix TC afferents in brain slices evoked responses mainly in superficial and deep layers, consistent with projection patterns of top-down afferents that carry visual information to auditory cortex. Responses to auditory stimuli in vivo and core TC afferents in brain slices were significantly less affected by isoflurane compared to responses triggered by visual stimuli in vivo and CC/matrix TC afferents in slices. At a just-hypnotic dose in vivo, auditory responses were enhanced by isoflurane, whereas visual responses were dramatically reduced. At a comparable concentration in slices, isoflurane suppressed both core TC and CC/matrix TC responses, but the effect on the latter responses was far greater than on core TC responses, indicating that at least part of the differential effects observed in vivo were due to local actions of isoflurane in auditory cortex. These data support a model in which disruption of top-down connectivity contributes to anesthesia-induced LOC, and have implications for understanding the neural basis of consciousness. 

Preferential effect of isoflurane on top-down vs. bottom-up pathways in sensory cortex.

The isolated forearm technique allows assessment of consciousness of the external world (connected consciousness) through a verbal command to move the hand (of a tourniquet-isolated arm) during intended general anesthesia. Previous isolated forearm technique data suggest that the incidence of connected consciousness may approach 37% after a noxious stimulus. The authors conducted an international, multicenter, pragmatic study to establish the incidence of isolated forearm technique responsiveness after intubation in routine practice.

Incidence of Connected Consciousness after Tracheal Intubation: A Prospective, International, Multicenter Cohort Study of the Isolated Forearm Technique.

-methyl-d-aspartate (NMDA) antagonists are widely used in anesthesia, pain management, and schizophrenia animal model studies, and recently as potential antidepressants. However, the mechanisms underlying their anesthetic, psychotic, cognitive, and emotional effects are still elusive. The basal ganglia (BG) integrate input from different cortical domains through their dopamine-modulated connections to achieve optimal behavior control. NMDA antagonists have been shown to induce gamma oscillations in human EEG recordings and in rodent cortical and BG networks. However, network relations and implications to the primate brain are still unclear. We recorded local field potentials (LFPs) simultaneously from the primary motor cortex (M1) and the external globus pallidus (GPe) of four vervet monkeys (26 sessions, 97 and 76 cortical and pallidal LFPs, respectively) before and after administration of ketamine (NMDA antagonist, 10 mg/kg im). Ketamine induced robust, spontaneous gamma (30-50 Hz) oscillations in M1 and GPe. These oscillations were initially modulated by ultraslow oscillations (~0.3 Hz) and were highly synchronized within and between M1 and the GPe (mean coherence magnitude = 0.76, 0.88, and 0.41 for M1-M1, GPe-GPe, and M1-GPe pairs). Phase differences were distributed evenly around zero with broad and very narrow distribution for the M1-M1 and GPe-GPe pairs (-3.5 ± 31.8° and -0.4 ± 6.0°), respectively. The distribution of M1-GPe phase shift was skewed to the left with a mean of -18.4 ± 20.9°. The increased gamma coherence between M1 and GPe, two central stages in the cortico-BG loops, suggests a global abnormal network phenomenon with a unique spectral signature, which is enabled by the BG funneling architecture. This study is the first to show spontaneous gamma oscillations under NMDA antagonist in nonhuman primates. These oscillations appear in synchrony in the cortex and the basal ganglia. Phase analysis refutes the confounding effects of volume conduction and supports the funneling and amplifying architecture of the cortico-basal ganglia loops. These results suggest an abnormal network phenomenon with a unique spectral signature that could account for pathological mental and neurological states.

Ketamine induced converged synchronous gamma oscillations in the cortico-basal ganglia network of nonhuman primates.

Warming intravenous fluids is essential to prevent hypothermia in patients with trauma, especially when large volumes are administered. Prehospital and transport settings require fluid warmers to be small, energy efficient and independent of external power supply. We compared the warming properties and resistance to flow of currently available battery-operated fluid warmers.

Comparison of the performance of battery-operated fluid warmers.

Heart rate variability (HRV) reflects cardiac and autonomic nervous system activity. It is usually measured over a relatively prolonged period and presented using multiple parameters. Here, we studied rapid HRV changes during airway obstruction using a short (1 min) sampling window. Forty healthy volunteers underwent a trial of obstructed breathing. Heart rate was recorded during three consecutive sets comprised of 1-min control followed by 1 min of obstructed breathing, with 1 min of rest between sets. Time and frequency domain analysis were used to compare HRV during control versus obstructed breathing. Compared with control, HRV intensely increased during obstructed breathing: R-R intervals (time between consecutive R waves) standard deviation increased from 65 to 108 msec (P < 0.0001), root mean square of successive R-R interval from 61 to 82 msec (P = 0.001), number of pairs of successive R-R intervals that differ by more than 50 msec (NN50) from 16.5 to 25.3 events (P < 0.0001), and proportion of NN50 divided by total number of R-R intervals from 26.6 to 35.1% (P = 0.001). Low frequency power increased by more than fourfold (P < 0.0001), allowing 90% sensitivity and 75% specificity for identifying airway obstruction (ROC area 0.88, P < 0.0001). We observed a rapid intense increase in HRV during obstructed breathing, significant enough to detect during a short 1-min sampling window. These findings suggest that HRV may be useful for rapid detection of airway obstruction, especially in situations where end-tidal CO monitoring is not optimal, such as during partial airway obstruction.

One-minute heart rate variability - an adjunct for airway obstruction identification.

Cesarean Delivery Under General Anesthesia Causing Autistic Spectrum Disorders: Not Very Likely.

Functional MRI and electrophysiology studies suggest that consciousness depends on large-scale thalamocortical and corticocortical interactions. However, it is unclear how neurons in different cortical layers and circuits contribute. We simultaneously recorded from central lateral thalamus (CL) and across layers of the frontoparietal cortex in awake, sleeping, and anesthetized macaques. We found that neurons in thalamus and deep cortical layers are most sensitive to changes in consciousness level, consistent across different anesthetic agents and sleep. Deep-layer activity is sustained by interactions with CL. Consciousness also depends on deep-layer neurons providing feedback to superficial layers (not to deep layers), suggesting that long-range feedback and intracolumnar signaling are important. To show causality, we stimulated CL in anesthetized macaques and effectively restored arousal and wake-like neural processing. This effect was location and frequency specific. Our findings suggest layer-specific thalamocortical correlates of consciousness and inform how targeted deep brain stimulation can alleviate disorders of consciousness.

Thalamus Modulates Consciousness via Layer-Specific Control of Cortex.

Transcatheter aortic valve implantation (TAVI) is used in patients with severe aortic stenosis (AS) who are at high surgical risk. Pre- and post-operative management is challenging as these patients are older, have significant comorbidities and a very high expected mortality rate in conventional surgery. There is no consensus in the literature about the preferred form of anesthesia, however, currently most centers perform the procedure using local anesthesia with sedation (LA-S).

[DIFFERENT ANESTHESIA APPROACHES IN THE TRANSCATHETER AORTIC VALVE IMPLANTATION (TAVI) PROCEDURE AND THEIR POSSIBLE EFFECT ON MORBIDITY AND MORTALITY].

Recent animal studies demonstrated neuronal apoptosis following early life exposure to most anesthetic drugs. Further research into this question demonstrated neonatal neuronal damage in multiple species (including primates) and evidence that this damage has cognitive and social sequela. These results raised the suspicion that general anesthesia in neonates, infants and pregnant women may injure the developing brain. Follow-up human studies were inconclusive. Retrospective studies suffer from tremendous selection bias due to the surgical effect and the baseline condition that required the surgical intervention. A number of large retrospective studies yield contradicting results, leaving the issue unsettled. Results of new, high quality prospective studies suggest that a short, single exposure does not lead to any measurable damage, but we are still awaiting final long term results. Despite the inconclusive evidence, the American Food and Drug Administration (FDA) published a warning mandating drug manufacturers to disclose the risk with the package insert, and clinicians to discuss the possible risks with the parents or the pregnant woman before the planned procedure. The European Society of Anesthesiologists, as well as the Israeli Society of Anesthesiologists, did not adopt this FDA policy. Despite the possible uncertain risk, it was decided that the evidence is inconclusive in regards to clinical human scenarios. It was agreed that such warnings would lead to delaying necessary procedures based on unfounded information. It was therefore decided to avoid changing the informed consent form and consent process until further information is available.

Aeyal Raz

Department of Anesthesiology

University of Wisconsin

Optogenetic Activation of Afferent Pathways in Brain Slices and Modulation of Responses by Volatile Anesthetics

Aeyal Raz

.css-o250i3{font-size:18px;font-family:Open Sans,sans-serif;line-height:21.6px;}Department of Anesthesiology

University of Wisconsin

Optogenetic Activation of Afferent Pathways in Brain Slices and Modulation of Responses by Volatile Anesthetics

Department of Anesthesiology