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

Dynamic Effective Connectivity of Inter-Areal Brain Circuits

Anatomic connections between brain areas affect information flow between neuronal circuits and the synchronization of neuronal activity. However, such structural connectivity does not coincide with effective connectivity (or, more precisely, causal connectivity), related to the elusive question “Which areas cause the present activity of which others?”. Effective connectivity is directed and depends flexibly on contexts and tasks. Here we show that dynamic effective connectivity can emerge from transitions in the collective organization of coherent neural activity. Integrating simulation and semi-analytic approaches, we study mesoscale network motifs of interacting cortical areas, modeled as large random networks of spiking neurons or as simple rate units. Through a causal analysis of time-series of model neural activity, we show that different dynamical states generated by a same structural connectivity motif correspond to distinct effective connectivity motifs. Such effective motifs can display a dominant directionality, due to spontaneous symmetry breaking and effective entrainment between local brain rhythms, although all connections in the considered structural motifs are reciprocal. We show then that transitions between effective connectivity configurations (like, for instance, reversal in the direction of inter-areal interactions) can be triggered reliably by brief perturbation inputs, properly timed with respect to an ongoing local oscillation, without the need for plastic synaptic changes. Finally, we analyze how the information encoded in spiking patterns of a local neuronal population is propagated across a fixed structural connectivity motif, demonstrating that changes in the active effective connectivity regulate both the efficiency and the directionality of information transfer. Previous studies stressed the role played by coherent oscillations in establishing efficient communication between distant areas. Going beyond these early proposals, we advance here that dynamic interactions between brain rhythms provide as well the basis for the self-organized control of this “communication-through-coherence”, making thus possible a fast “on-demand” reconfiguration of global information routing modalities

EEG, MEG and neuromodulatory approaches to explore cognition: Current status and future directions

Neural oscillations and their association with brain states and cognitive functions have been object of extensive investigation over the last decades. Several electroencephalography (EEG) and magnetoencephalography (MEG) analysis approaches have been explored and oscillatory properties have been identified, in parallel with the technical and computational advancement. This review provides an up-to-date account of how EEG/MEG oscillations have contributed to the understanding of cognition. Methodological challenges, recent developments and translational potential, along with future research avenues, are discussed. Keywords: Cognition; Electrophysiology; Event-related-potentials; Neural oscillations; Neural synchronisation; Neuromodulatio

Fractals in the Nervous System: conceptual Implications for Theoretical Neuroscience

This essay is presented with two principal objectives in mind: first, to document the prevalence of fractals at all levels of the nervous system, giving credence to the notion of their functional relevance; and second, to draw attention to the as yet still unresolved issues of the detailed relationships among power law scaling, self-similarity, and self-organized criticality. As regards criticality, I will document that it has become a pivotal reference point in Neurodynamics. Furthermore, I will emphasize the not yet fully appreciated significance of allometric control processes. For dynamic fractals, I will assemble reasons for attributing to them the capacity to adapt task execution to contextual changes across a range of scales. The final Section consists of general reflections on the implications of the reviewed data, and identifies what appear to be issues of fundamental importance for future research in the rapidly evolving topic of this review

Effect of Social Status on the Behavior and Neurophysiology of Crayfish

Adaptation to changing social conditions is important for many social animals. Here, the effects of social experience on the behavior and neurophysiology of the red swamp crayfish, Procambarus clarkii, were studied. Evidence is presented that shows juvenile crayfish interact and form social order, and their behavior patterns shift in accordance to social status. Dominant animals maintain a high level of aggressive behavior, while subordinates shift their behavior pattern from aggressive to submissive behavior. Adult male crayfish show similar behavior pattern during dominance formation. However, this work demonstrates that male crayfish adopt a unique strategy to signify the formation of a social order expressed in the form of pseudocopulation. Pseudocopulation between male crayfish signifies the acceptance of the social status and leads to the reduction of aggression of dominants and enhances the survival of subordinate animals. I investigated the long-term effects of social status on the behavioral and physiological responses of crayfish to unexpected sensory touch. I discovered that animals of different social experience display different orienting responses that correlate with in vivo electromyographic recordings from the legs’ depressor muscle. The status-dependent response patterns observed in vivo are retained in a reduced, in vitro, preparation that lacks descending input from the brain. The role of serotonin (5-HT) was investigated in mediating the motor output patterns of the depressor nerve. Putative serotonergic innervations of the depressor nerve were identified that originate from serotonergic neurons located in the first abdominal ganglion. Selective stimulation of the ipsilateral 5-HT neuron enhances the response of the depressor nerve to sensory stimulation. Application of 5-HT modestly increased the tonic firing activity of the depressor nerve in social isolates and subordinates but significantly decreased the activity in dominants. This work illustrates that the formation of a dominance relationship significantly and immediately alters the behavior of the participants. As the social relationship matures, the social experience that develops affects the underlying neurophysiology that mediates the behavior. It will be of great interest in future studies to identify not only the effects rather the mechanisms of how social experience induces physiological changes

EEG-based investigation of cortical activity during Postural Control

The postural control system regulates the ability to maintain a stable upright stance and to react to changes in the external environment. Although once believed to be dominated by low-level reflexive mechanisms, mounting evidence has highlighted a prominent role of the cortex in this process. Nevertheless, the high-level cortical mechanisms involved in postural control are still largely unexplored. The aim of this thesis is to use electroencephalography, a widely used and non-invasive neuroimaging tool, to shed light on the cortical mechanisms which regulate postural control and allow balance to be preserved in the wake of external disruptions to one’s quiet stance. EEG activity has been initially analysed during a well-established postural task - a sequence of proprioceptive stimulations applied to the calf muscles to induce postural instability – traditionally used to examine the posturographic response. Preliminary results, obtained through a spectral power analysis of the data, highlighted an increased activation in several cortical areas, as well as different activation patterns in the two tested experimental conditions: open and closed eyes. An improved experimental protocol has then been developed, allowing a more advanced data analysis based on source reconstruction and brain network analysis techniques. Using this new approach, it was possible to characterise with greater detail the topological structure of cortical functional connections during the postural task, as well as to draw a connection between quantitative network metrics and measures of postural performance. Finally, with the integration of electromyography in the experimental protocol, we were able to gain new insights into the cortico-muscular interactions which direct the muscular response to a postural challenge. Overall, the findings presented in this thesis provide further evidence of the prominent role played by the cortex in postural control. They also prove how novel EEG-based brain network analysis techniques can be a valid tool in postural research and offer promising perspectives for the integration of quantitative cortical network metrics into clinical evaluation of postural impairment.Kerfi stöðustjórnunar er afturvirkt stýrikerfi sem vinnur stöðugt að því að viðhalda uppréttri stöðu líkamans og bregðast við ójafnvægi. Vaxandi þekking á undanförnum árum hefur lýst því að úrvinnsla þessara upplýsinga á sér stað á öllum stigum miðtaugakerfisins, þá sérstaklega barkarsvæði heilahvela. Engu að síður, er nákvæmu hlutverk heilabarkar við stöðustjórnun enn óljóst að mörgu leyti. Tilgangur þessa verkefnis var að rannsaka nánar hlutverk heilabarkar við truflun og áreiti á kerfi stöðustjórnarinnar, með notkun hágæða heilarafrits (EEG). Við byrjuðum á því að mæla heilarit einstaklinga meðan á þekktri líkamsstöðu-æfingu stóð, til þess að skoða svörun líkamans við röð titringsáreita sem beitt var á kálfavöðvana til að framkalla óstöðugleika. Bráðabirgðaniðurstöður fengnar með PSD-aðferð (power spectral analysis) leiddu í ljós aukna virkni á ákveðnum svæðum í heilaberki og sérstakt viðbragðsmynstur við að framkvæma æfinguna, annars vegar með lokuð augu og hins vegar opin augu. Rannsókn okkar hélt áfram með nýrri og þróaðari tækni sem gerði okkur kleift að framkvæma fullkomnari greiningaraðferðir til að túlka, greina og skilja merki frá heilaritnu. Með fullkomnari greiningaraðferðum var hægt að lýsa með nákvæmari hætti staðfræðilega uppbyggingu starfrænna tenginga í heilaberki meðan á líkamsstöðu æfingunni stóð, sem og að draga tengsl á milli megindlegra netmælinga og mælinga á líkamsstöðu. Að lokum bætist við vöðvarafritsmæling við aðferðafræðina, sem gaf okkur innsýn inn í samskipti heilabarka og vöðvana sem stýra vöðvaviðbrögðum og viðhalda líkamsstöðu við utanaðkomandi áreiti. Á heildina litið gefa niðurstöðurnar sem settar eru fram í þessari ritgerð enn sterkari vísbendingar um það áberandi hlutverk sem heilabörkurinn gegnir við stjórnun líkamsstöðu. Niðurstöðurnar sanna einnig hvernig ný aðferð á greiningu á tengslaneti heilans sem byggir á heilariti getur verið gilt tæki í líkamsstöðu rannsóknum og er nytsamlegt tól fyrir mælingar á heilakerfisneti í klínískt mat á skerðingu líkamsstöðu