The (un)conscious mouse as a model for human brain functions: key principles of anesthesia and their impact on translational neuroimaging

In recent years, technical and procedural advances have brought functional magnetic resonance imaging (fMRI) to the field of murine neuroscience. Due to its unique capacity to measure functional activity non-invasively, across the entire brain, fMRI allows for the direct comparison of large-scale murine and human brain functions. This opens an avenue for bidirectional translational strategies to address fundamental questions ranging from neurological disorders to the nature of consciousness. The key challenges of murine fMRI are: (1) to generate and maintain functional brain states that approximate those of calm and relaxed human volunteers, while (2) preserving neurovascular coupling and physiological baseline conditions. Low-dose anesthetic protocols are commonly applied in murine functional brain studies to prevent stress and facilitate a calm and relaxed condition among animals. Yet, current mono-anesthesia has been shown to impair neural transmission and hemodynamic integrity. By linking the current state of murine electrophysiology, Ca(2+) imaging and fMRI of anesthetic effects to findings from human studies, this systematic review proposes general principles to design, apply and monitor anesthetic protocols in a more sophisticated way. The further development of balanced multimodal anesthesia, combining two or more drugs with complementary modes of action helps to shape and maintain specific brain states and relevant aspects of murine physiology. Functional connectivity and its dynamic repertoire as assessed by fMRI can be used to make inferences about cortical states and provide additional information about whole-brain functional dynamics. Based on this, a simple and comprehensive functional neurosignature pattern can be determined for use in defining brain states and anesthetic depth in rest and in response to stimuli. Such a signature can be evaluated and shared between labs to indicate the brain state of a mouse during experiments, an important step toward translating findings across species

Psychophysiological indices of recognition memory

It has recently been found that during recognition memory tests participants’ pupils dilate more when they view old items compared to novel items. This thesis sought to replicate this novel ‘‘Pupil Old/New Effect’’ (PONE) and to determine its relationship to implicit and explicit mnemonic processes, the veracity of participants’ responses, and the analogous Event-Related Potential (ERP) old/new effect. Across 9 experiments, pupil-size was measured with a video-based eye-tracker during a variety of recognition tasks, and, in the case of Experiment 8, with concurrent Electroencephalography (EEG). The main findings of this thesis are that: - the PONE occurs in a standard explicit test of recognition memory but not in “implicit” tests of either perceptual fluency or artificial grammar learning; - the PONE is present even when participants are asked to give false behavioural answers in a malingering task, or are asked not to respond at all; - the PONE is present when attention is divided both at learning and during recognition; - the PONE is accompanied by a posterior ERP old/new effect; - the PONE does not occur when participants are asked to read previously encountered words without making a recognition decision; - the PONE does not occur if participants preload an “old/new” response; - the PONE is not enhanced by repetition during learning. These findings are discussed in the context of current models of recognition memory and other psychophysiological indices of mnemonic processes. It is argued that together these findings suggest that the increase in pupil-size which occurs when participants encounter previously studied items is not under conscious control and may reflect primarily recollective processes associated with recognition memory

Optimizing Circadian Rhythm and Characterizing Brain Function in Disorders of Consciousness

Sleep is a physiological state where memory processing, learning and brain plasticity occur. Patients with prolonged disorders of consciousness (PDOC) show no or minimal signs of awareness of themselves or their environment but appear to have sleep-wake cycles. The main aim of this thesis was to investigate effect of circadian rhythm and sleep optimization on brain functions of patients with PDOC. In the first instance, sleep and circadian rhythms of patients with PDOC were investigated using polysomnography and saliva melatonin measurements. The investigations that were performed at the baseline suggested that both circadian rhythmicity and sleep were severely deranged in PDOC patients. This was followed by the interventional stage of the research where an attempt was made to optimize circadian rhythm and sleep by giving blue light, caffeine and melatonin in a small cohort of patients. To measure the effects of the intervention, we used a variety of assessments: Coma Recovery Scale-Revised (CRS-R) to measure changes in awareness; PSG for assessment of sleep, melatonin for assessment of circadian rhythm; and, event-related potential measures including mismatch negativity (MMN) and subject’s own name (SON) paradigms. Our results showed that it is possible to improve sleep and circadian rhythms of patients with PDOC, and most importantly, this improvement leads to increase in Coma Recovery Scale-Revised scores. Individually, those patients who responded well to the intervention also showed improvements in their functional brain imaging assessments

Multi-band SWIFT enables quiet and artefact-free EEG-fMRI and awake fMRI studies in rat

Functional magnetic resonance imaging (fMRI) studies in animal models provide invaluable information regarding normal and abnormal brain function, especially when combined with complementary stimulation and recording techniques. The echo planar imaging (EPI) pulse sequence is the most common choice for fMRI investigations, but it has several shortcomings. EPI is one of the loudest sequences and very prone to movement and susceptibility-induced artefacts, making it suboptimal for awake imaging. Additionally, the fast gradient-switching of EPI induces disrupting currents in simultaneous electrophysiological recordings. Therefore, we investigated whether the unique features of Multi-Band SWeep Imaging with Fourier Transformation (MB-SWIFT) overcome these issues at a high 9.4 T magnetic field, making it a potential alternative to EPI. MB-SWIFT had 32-dB and 20-dB lower peak and average sound pressure levels, respectively, than EPI with typical fMRI parameters. Body movements had little to no effect on MB-SWIFT images or functional connectivity analyses, whereas they severely affected EPI data. The minimal gradient steps of MB-SWIFT induced significantly lower currents in simultaneous electrophysiological recordings than EPI, and there were no electrode-induced distortions in MB-SWIFT images. An independent component analysis of the awake rat functional connectivity data obtained with MB-SWIFT resulted in near whole-brain level functional parcellation, and simultaneous electrophysiological and fMRI measurements in isoflurane-anesthetized rats indicated that MB-SWIFT signal is tightly linked to neuronal resting-state activity. Therefore, we conclude that the MB-SWIFT sequence is a robust preclinical brain mapping tool that can overcome many of the drawbacks of conventional EPI fMRI at high magnetic fields.peerReviewe

A Personalized Medicine Approach to the Diagnosis and Management of Autism Spectrum Disorder

This collection of articles provides an overview of the current and future methods for applying a personalized medicine approach to the diagnosis, management, and treatment of autism spectrum disorder