Locus coeruleus norepinephrine activity mediates sensory-evoked awakenings from sleep

A defining feature of sleep is reduced responsiveness to external stimuli, but the mechanisms mediating sensory-evoked arousal remain unclear. We hypothesized that reduced locus coeruleus (LC) norepinephrine (NE) activity during sleep mediates unresponsiveness, and its action promotes sensory-evoked awakenings. We tested this using electrophysiological, behavioral, pharmacological, and optogenetic techniques alongside auditory stimulation in freely behaving rats. We found that systemic reduction in NE signaling lowered probability of sound-evoked awakenings (SEAs). The level of tonic LC activity during sleep anticipated SEAs. Optogenetic LC activation promoted arousal as evident in sleep-wake transitions, EEG desynchronization, and pupil dilation. Minimal LC excitation before sound presentation increased SEA probability. Optogenetic LC silencing using a soma-targeted anion-conducting channelrhodopsin (stGtACR2) suppressed LC spiking and constricted pupils. Brief periods of LC opto-silencing reduced the probability of SEAs. Thus, LC-NE activity determines the likelihood of sensory-evoked awakenings, and its reduction during sleep constitutes a key factor mediating behavioral unresponsiveness.This work was supported by the Israel Science Foundation (ISF) grants 1326/15 and 51/11 (I-CORE cognitive sciences) and the Adelis Foundation (to Y.N.). E.J.K. is an INSERM fellow. O.Y. is supported by the European Research Council (ERC-2013-StG OptoNeuromod 337637) and the Adelis Foundation. CAV2 vector production was supported by CNRS BioCampus (Montpellier). A.S. is a Wellcome Trust-funded PhD student on the Neural Dynamics program. A.J.K. is supported by the ISF grant 762/16 and the European Society of Anaesthesiology young investigator startup gran

Intraoperative neurophysiological monitoring of the ocular vestibular evoked myogenic potential (oVEMP): a novel implementation to detect vestibular and oculomotor pathway dysfunction during brainstem surgery

Different intraoperative neurophysiological monitoring techniques can be used to assess the functional integrity of the brainstem during neurosurgical procedures that put the delicate neurovascular structures of the brainstem at risk. Whilst each individual technique has its benefits and limitations, multimodal monitoring can offer a near real-time comprehensive assessment of the neural pathways under investigation. However, not all the pathways that are at risk during tumour resection are able to be assessed with the currently available techniques. The pathways that convey the vestibulo-ocular reflex, which is responsible for stabilisation of a steady visual image on the retina during movement of the head and body can be disrupted during surgery to remove tumours within the cerebellar-pontine fossa. This disturbance in transmission can lead to disabling gaze deficits and vestibular disturbances. The ocular vestibular evoked myogenic potential (oVEMP) that can be recorded from the contralateral inferior oblique muscle after air conducted stimulation describes the excitation of this reflex. The oVEMP is mediated via the ascending utricle fibres that connect to the ipsilateral vestibular nuclei and project, via a crossed reflex pathway in the medial longitudinal fascicule in the brainstem, to the contralateral oculomotor nucleus to elicit an excitatory muscle response. Objective: To determine if oVEMPs could be recorded intraoperatively. To investigate whether changes in amplitude and/or latency correlated with post-operative vestibular pathway dysfunction in those patients undergoing cerebellopontine angle surgery. Methods: This observational study incorporated 37 patients who were monitored neurophysiologically during brainstem surgery with additional oVEMPs recordings. The sensitivity and specificity of the amplitude decrement of the oVEMP was determined. Results: Intraoperative oVEMPs were able to be recorded in 31 patients. 21/22 patients who did not show any changes in the oVEMP did not experience any immediate or long term relevant clinical deficit. Eight patients showed immediate post-operative vestibulo-ocular dysfunction with seven of them showing accompanying oVEMP changes. The sensitivity, specificity, and positive and negative predictive values for the oVEMPs to detect vestibular ocular dysfunction in the immediate post-operative period were 75%, 91.3%, 75% and 91.3% respectively, with a test accuracy of 87.1%. Conclusion: Changes in the oVEMP amplitude <50% (which did not reverse), or loss of the potential intraoperatively, predict post-operative deficits of the vestibulo-ocular pathway. Significance: The oVEMP is able to be recorded in patients undergoing brainstem surgery to monitor the integrity of the vestibular portion of the eighth cranial nerve, the medial longitudinal fascicule within the brainstem and the oculomotor cranial nerve pathway. Monitoring of this potential intraoperatively may enhance the safety of cerebellar pontine angle surgery

Suitability of the dorsal column nuclei for a neural prosthesis: functional considerations

The brainstem dorsal column nuclei (DCN) may be an ideal target for a future neural prosthesis to restore somatosensation in tetraplegic patients. We aimed to investigate the functional and structural characteristics of the DCN, with the overarching goal of determining their suitability as a somatosensory neural prosthetic target. First, we review the neuroanatomy of the DCN and surrounding nuclei, including the cuneate, gracile, external cuneate, X, and Z nuclei, which together comprise the DCN-complex. We reveal that the DCN are not organised to only process and relay tactile information, as is commonly thought, but instead are a complex sensorimotor integration and distribution hub, with diverse projection targets throughout the hindbrain and midbrain. Next, we sought to show that somatosensory signals arriving in the DCN are reproducible, and that they carry decodable information about the location and quality of somatosensory stimuli, which we propose are necessary conditions for a potential somatosensory neural prosthetic target. We record somatosensory-evoked signals from various locations across the surface of the DCN in 8-week-old anaesthetised male Wistar rats. We characterised somatosensory-evoked DCN surface signals and demonstrated that they have robust and reproducible high-frequency and low-frequency features within and across animals. Using a machine-learning approach, we developed a metric for evaluating the relevance of machine-learning inputs to target outputs, which we coined feature-learnability. Using feature-learnability allowed us to determine the DCN signal features that were most relevant to peripheral somatosensory events, which facilitated very high accuracy prediction of the location and quality of somatosensory events, from small numbers of features. This thesis supports the DCN as a potential somatosensory neural prosthetic target by: i) showing DCN connectivity with sensorimotor targets essential for movement modulation in conscious and non-conscious neural pathways; ii) determining DCN signal features that are most relevant to peripheral tactile and proprioceptive events. New knowledge about the most relevant DCN signal features may inform the development of biomimetic stimulus patterns designed to artificially activate the DCN in future neural prosthetic devices for restoring somatosensory feedback

The Inferior Colliculus: A Target for Deep Brain Stimulation for Tinnitus Suppression

University of Minnesota Ph.D. dissertation. August 2015. Major: Biomedical Engineering. Advisor: Hubert Lim. 1 computer file (PDF); xii, 173 pages.Tinnitus is a neurological condition that manifests as a phantom auditory perception in the absence of an external sound source. Tinnitus is often caused by hearing loss associated with noise exposure or aging and as such, the prevalence is only expected to rise in the coming years. Currently there is no cure for tinnitus and available treatment options have only shown limited success, thus there is an ever present need for continued research into new treatments. In this thesis we propose a new approach to treating tinnitus that uses deep brain stimulation to target the inferior colliculus (IC) with the goal of altering tinnitus-related neural activity, such as hyperactivity and increased neural synchrony, to suppress the tinnitus percept. We hypothesize that stimulation of the outer cortices of the inferior colliculus will modulate the tinnitus-affected neurons in the central region of the inferior colliculus (ICC) and in turn, these neural changes will be carried throughout the central auditory system by the extensive projection network originating in the IC, and will induce modulation in other tinnitus-affected auditory nuclei. The research of this thesis is aimed at determining the feasibility of this tinnitus treatment by assessing the IC as a potential neuromodulation target and identifying optimal stimulation locations and stimulation strategies for achieving maximal suppression. The first study was completed to better understand the auditory coding properties of the IC and to create a three dimensional reconstruction of these functional properties across the entire IC. These results narrowed down the stimulation target to the dorsal cortex of the inferior colliculus (ICD) and produced a tool that could be used to consistently place stimulating and recording electrodes in correct regions in the IC. The second and third studies focused on assessing the best stimulation locations and stimulation paradigms within the ICD, respectively, by stimulating throughout and measuring changes in neural activity in the ICC. These results show that maximal suppression is achieved by stimulation of the rostral-medial region of the ICD using either electrical stimulation only or electrical stimulation paired with acoustic stimulation with an 18 ms delay. These results will guide implementation in human patients. There are already deaf patients who suffer from tinnitus that are being implanted with a deep brain stimulator for hearing restoration called the auditory midbrain implant. Hardware modifications to the auditory midbrain implant have been completed that will allow us to stimulate the ICD and evaluate the effects on the tinnitus percept directly in patients

Integrative function in rat visual system

A vital function of the brain is to acquire information about the events in the environment and to respond appropriately. The brain needs to integrate the incoming information from multiple senses to improve the quality of the sensory signal. It also needs to be able to distribute the processing resources to optimise the integration across modalities based on the reliability and salience of the incoming signals. This thesis aimed to investigate two aspects of the way in which the brain integrates information from the external environment: multisensory integration and selective attention. The hooded rat was used as the experimental animal model. In Chapter 2 of this thesis, I investigate the multisensory properties of neurons in superior colliculus (SC), a midbrain structure involved in attentive and orienting behaviours. I first establish that in rat SC, spiking activity is elevated by whisker or visual stimuli, but rarely both, when those stimuli are presented in isolation. I then show that visually responsive sites are mainly found in superficial layers whereas whisker responsive sites were in intermediate layers. Finally I show that there are robust suppressive interactions between these two modalities. In Chapter 3, I develop a rodent behavioural paradigm that can easily be paired with electrophysiological measurements. The design is adaptable to a variety of detection and discrimination tasks. Head position is restricted in the central nose-poke without head-fixation and the eyes can be constantly monitored via video camera. In Chapter 4, I ask whether selective spatial visual attention can be demonstrated in rats utilising the paradigms developed in Chapter 3. Selective attention is the process by which brain focuses on significant external events. Does being able to predict the likely side of the stimulus modulate the speed and accuracy of stimulus detection? To address this question, I varied the probability with which the signal was presented on left or right screen. My results suggest that rats have the capacity for spatial attention engaged by top-down mechanisms that have access to the predictability of stimulus location. In summary, my thesis presents a paradigm to study visual behaviour, multisensory integration and selective spatial attention in rats. Over the last decade, rats have gained popularity as a viable animal model in sensory systems neuroscience because of the access to the array of genetic tools and in vivo electrophysiology and imaging techniques. As such the paradigms developed here provide a useful preparation to complement the existing well-established primate models

Intraoperative Neurophysiological Monitoring for Endoscopic Endonasal Approaches to the Skull Base: A Technical Guide.

Intraoperative neurophysiological monitoring during endoscopic, endonasal approaches to the skull base is both feasible and safe. Numerous reports have recently emerged from the literature evaluating the efficacy of different neuromonitoring tests during endonasal procedures, making them relatively well-studied. The authors report on a comprehensive, multimodality approach to monitoring the functional integrity of at risk nervous system structures, including the cerebral cortex, brainstem, cranial nerves, corticospinal tract, corticobulbar tract, and the thalamocortical somatosensory system during endonasal surgery of the skull base. The modalities employed include electroencephalography, somatosensory evoked potentials, free-running and electrically triggered electromyography, transcranial electric motor evoked potentials, and auditory evoked potentials. Methodological considerations as well as benefits and limitations are discussed. The authors argue that, while individual modalities have their limitations, multimodality neuromonitoring provides a real-time, comprehensive assessment of nervous system function and allows for safer, more aggressive management of skull base tumors via the endonasal route