Andreas A. Ioannides, Gregoris A. Orphanides and Lichan Liu

Abstract:

Laboratory for Human Brain Dynamics, AAI Scientific Cultural Services Ltd., Nicosia, Cyprus

Background: The introduction of formal criteria for sleep staging in the 1960s (Rechtschaffen and Kales, 1968) revolutionised the study of sleep. A massive volume of hypnograms (formal sleep records) has been amassed and is used routinely in sleep medicine and basic research.

The classical sleep staging criteria relied on visual inspection of the electroencephalography (EEG) record. Sleep experts identified high amplitude and/or highly rhythmic events that were defined as the hallmarks of each distinct sleep stages. Critically quiet periods between such events inherited the sleep stage label of the previous period. This collection of rules provided the first principled and reproducible characterisation of sleep. Nevertheless, viewed from today’s vantage view, the original sleep staging criteria were limited by the low quality of the EEG signal available over half a century ago. Today, these limitations are too obvious to ignore. Yet, recent changes in the criteria (Silber et al., 2007) do not address fundamental deficiencies, because their main goal is to improve the agreement amongst experts with practically no effort to exploit recent advances in sleep EEG and neuroimaging recordings and analysis. Next, we report our recent finding with the latest ones representing the collateral output of our search for human ponto-geniculate-occipital (PGO) waves guided by recent reports linking PGOs to heart rate (HR) surges (HRS) (Rowe et al., 1999)

Objective: Looking at the progression of our work retrospectively, we recognise both an element of serendipity from our ongoing hunt for human PGO waves. This has accelerated the almost inevitable eventual fall into the attractor of the lasting objective: to advance sleep staging in a principled way, based on sleep physiology, while preserving continuity with the rich earlier records obtained with traditional sleep staging criteria.

Methods and Results: The details of the work are already out (Ioannides et al., 2022b), which allows us to focus this short description on the distinct conceptual advances and the underlying logic of the findings. The distinct conceptual advances were:

 The realization that at least some of, probably all, hallmarks of sleep stages do not have constant features or generators (at the time of the prominent EEG signal) and they do not represent brain wide reproducible excitation patterns. They are chaotic occurrences. They probably represent the rise to a chaotic and unstable period which on completion returns back to equilibrium (Dehghani et al., 2010; Frauscher et al., 2015; Ioannides et al., 2017, 2019). The only available candidates for such an equilibrium state are the quiet periods of the corresponding sleep stage.

 The key conjecture is that the quiet periods are far from boring and uninteresting; they represent the foundational or “core” periods of each sleep stage. Therefore, studying the core periods could help us understand sleep, in a similar way, the study of the ground state of atoms helped us understand chemistry. In a move towards validating this conjecture, tomographic analysis was performed and already demonstrated that core periods have their own signatures that can:

o Distinguish as well, if not better the sleep stages defined by the hallmarks.

o Using core periods, it is possible to extend the characterisation into periods when sleep is disturbed and to describe transitions between sleep stages (Ioannides et al., 2022a).

o Reveal an orderly and monotonic increase in the gamma band activity in one frontal and one posterior midline dorsal areas: from awake to light and then deep sleep, culminating in a crescendo of activity during REM sleep (Ioannides et al., 2009). The identified dorsal midline areas were interpreted as the closest we are likely to come to a neural representation of self (Ioannides, 2018).

o For the hallmarks studied so far, the key precursors were identified by comparing the period before each hallmark with the core period of the sleep stage it defines. The analysis showed in each case that the chaotic periods are preceded by activity in specific brain areas, which are their putative generators.

 The analysis of core periods of sleep stages has advanced our understanding of sleep, but did not remove the limitations of classical sleep stages. A detail analysis of the sleep stages and other auxiliary channels, particularly the electrocardiogram (ECG), revealed an anomaly in the classical sleep staging which showed most prominently during HRS. This anomaly could be removed by defining a new period of sleep, REM0, on the basis of simple criteria based on the variance of HR and the variance of one more electrophysiological measure (EEG, MEG or EMG) (Ioannides et al., 2022b).

Conclusions: For now, REM0 can be added, as an additional label, to the classical sleep stages to ensure continuity with the huge reservoir of hypnograms based on the classical sleep staging criteria. The association of REM0 with classical sleep staging, together with other suggestions (Simor et al., 2020) can also lead to a staged and orderly transition to a new sleep staging system if the claim of REM0 as a putative new sleep stage is validated.

Acknowledgements: Different parts of the research benefitted from work for European Space Agency (ESA, contract CY2_02 (4000127142) NEA2RS) and support from the European Regional Development Fund and the Republic of Cyprus (GRATOS EXCELLENCE/1216/0207 and CAVER COMPLEMENTARY/0916/0174). Mr. Matthew Fenech also contributed to this research under the EU Horizon project HOPE (grant number: 823958). Opinions expressed belong solely to the authors.

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Grigorios Kyriatzis, Invited Speech, Abstract

Abstract:

Neuroplasticity, the flexibility & adaptability of the brain after inflammation or injury at the central nervous system (CNS) or peripheral tissues, among others, occurs through changes in gene expression that involve neuroplastic changes (positive): synaptic long-term potentiation, reduced neuronal excitability, increased inhibition and neurogenesis (in neurodegenerative diseases). Valence, the positive or negative associative learning, that is paramount for survival, is an example of neuroplasticity mediated by synaptic plasticity onto divergent paths. In the CNS, these changes derive primarily from neuropeptides (or neuroactive peptides). Neurotensin (NT) is an endogenous neuropeptide, neurotransmitter and neuromodulator. It mediates both central and peripheral effects, among others analgesia, ethanol and addictive drug abuse, valence, and has been involved in a number of pathologies including stress/valence-related disorders. NT mediates its effects upon binding on 3 distinct receptor subtypes (NTSRs), NTSR1, NTSR2 and NTSR3. The NT system induces positive neuroplastic changes in various brain areas.

A negative form of neuroplasticity is neuroinflammation, that arises from dysregulation of activated glial cells and neuromodulators that they induce, that contribute to a variety of negative neuroplastic changes: synaptic dysregulations, enhanced neuronal excitability and reduced inhibition. We have recently shown that NTSR2 is highly expressed during neuroinflammation occurring post epilepsy and NTSR2 blockade reduces inflammation in glial cells in vitro. The strong inflammatory response is one of the main causes behind neurodegeneration that takes place in CNS diseases. The discovery of new drugs aiming at the constraint of neuroinflammation may prove to be a valuable treatment strategy.

Kostas Nizamis, Invited Speech, Abstract

Abstract:

The hand is a very complex and versatile tool, which allows humans to interact with their immediate environment, engage in daily life activities and socialize. Individuals with Duchenne muscular dystrophy (DMD), experience years of deteriorated hand function, leading to severe dependence on caregivers. Robotic exoskeletons can provide a feasible solution for the active hand support of individuals with DMD. My work describes the development of a hand exoskeleton that meets the specific needs of individuals with DMD, in order to raise their quality of life and social participation and acceptance.

To this end, in the Symbionics project we developed the SymbiHand orthosis; an active wearable hand exoskeleton for people with DMD. My role in this project was the characterization of the hand neuro-motor function in DMD and the development and application of robust hand motor intention decoding, for the control of the SymbiHand.

Petra Ritter, Invited Speech, Abstract

Abstract:

Virtual Brain Cloud generates multilevel virtual brains of patients and healthy human controls for research and innovation. Brain data from multiple sources are being pre-processed and annotated with a common data model – such that they all relate to common spatial reference frameworks. The platform thus offers a next generation clinical research infrastructure – compliant with EU Data Protection Regulations and creates an open yet protected space for groundbreaking digital health innovation.