Due to its complex and multifaceted nature, developing effective treatments for epilepsy is still a major challenge. To deal with this complexity we introduce the concept of degeneracy to the field of epilepsy research: the ability of disparate elements to cause an analogous function or malfunction. Here, we review examples of epilepsy-related degeneracy at multiple levels of brain organisation, ranging from the cellular to the network and systems level. Based on these insights, we outline new multiscale and population modelling approaches to disentangle the complex web of interactions underlying epilepsy and to design personalised multitarget therapies. This Perspective outlines the concept of degeneracy as it applies to seizures and epilepsy, and emphasizes how this concept should be an important consideration across cellular, network and systems levels of research. Degeneracy  should be distinguished from redundancy, which results from multiple identical elements performing the same function6, but see also ref. 7. In contrast to redundant components, degenerate components may generate dissimilar outputs in different contexts8. Therefore, although degeneracy is sometimes called also ‘partial redundancy’9, we follow the terminology of Edelman and Gally1 and distinguish degeneracy from redundancy.Degeneracy, “the ability of elements that are structurally different to perform the same function or yield the same output”10 and robustness13. Degeneracy allows organisms to satisfy the two seemingly contradictory goals of preserving already evolved functions and concurrently searching for and evolving new functions10. In this way degeneracy is linked to both robustness and innovation in evolution10.The ubiquity of degeneracy is rooted in the advantages it entails for organisms’ evolvability17, with similar physiological states arising from a multitude of different subcellular, cellular and synaptic mechanisms19, for recent reviews see refs. 21. However, not only similar physiological but also similar pathological brain states may arise from structurally disparate mechanisms23. Therefore, the existence of degeneracy in the brain has important implications for understanding and treating complex brain disorders such as epilepsy.It is becoming increasingly clear that the brain also exhibits degeneracy26, its complex multicausal and variable nature30 has made it difficult to disentangle the underlying mechanisms. This has hindered the development of effective therapies. Apparently contradictory observations still fuel deep controversies about the origin of epilepsy. In this review, we argue that competing hypotheses can be reconciled by taking into account the concept of degeneracy. Moreover, we emphasize that degeneracy can help explain why multiple minor changes can sometimes induce pathological phenotypes, while at other times their effects cancel, preserving healthy/physiological circuit states.Despite considerable progress in epilepsy research, reviewed byOur aim is to review examples for epilepsy-related degeneracy at three different levels of brain organization: the cellular, network and systems level. We propose that epilepsy is a group of multiscale disorders with a potential involvement of degenerate mechanisms at each level see Fig. .Fig. 1De32. This phenomenon has been termed ion channel degeneracy34; for recent reviews see refs. 23. Ion channel degeneracy means that “distinct channel types overlap in their biophysical properties and can thus contribute collectively to specific physiological phenotypes”23.It is now well established that indistinguishable single-cell and network activity can result from a variety of parameter combinations of different ion channels37. However, their role in the context of ion channel degeneracy and epilepsy has not yet been studied extensively. Neuronal hyperexcitability and associated epilepsy often arise as a result of combinatorial effects of multiple ion channel mutations. This has been demonstrated by an important sequencing study by Klassen et al., examining over 200 ion channel genes in epilepsy patients and healthy controls38. The study found a highly complex pattern of gene changes in single individuals. Even multiple nonsynonymous mutations in known monogenic risk genes for epilepsy were frequently identified in healthy individuals38  often fails to detect mutations in known disease-causing genes, despite an intensive search for monogenic causes in affected families. This suggests polygenic inheritance of these classic genetic epilepsies. The difficulty in finding the contributing genes in these patients is probably related to the multicausal nature of their epilepsy.38 indicate that epilepsies are more often caused by an accumulation of mutations in multiple ion channels than by mutation in one particular ion channel39.The results of Klassen et al.40. The degeneracy of ion channels may also explain why in some individuals a lower number of mutations or hits leads to a pathological epilepsy phenotype, while other individuals with a higher number of hits appear unaffected23. The net effect of combined mutations will depend, first, on the initial, pre-mutation distance of a given individual (i.e. a given set of ion channel parameters) from the pathological hyperexcitable region of the possible functional space. Second, the net effect will depend on the specific trajectory in functional space determined by single or multiple mutations  as well as intrinsic properties belong to important degenerate parameters of the circuit112. Therefore, in principle, synaptic mechanisms can compensate for the impaired function of intrinsic ion channels and vice versa111, thus increasing the robustness of the nervous system23 by counterbalancing changes in overall synaptic drive and intrinsic excitability113.Degeneracy can be found not only at the single cell level but also at the network level of synaptically connected neurons. Analogous to multiple configurations of intrinsic ion channels leading to indistinguishable electrical behavior of single neurons42. The sparsely active dentate gyrus is considered a protective gate for the spread of epilepsy-related hyperexcitability in the hippocampus116. The degeneracy hypothesis predicts that effective protection of the dentate gate is supported by degenerate intrinsic and synaptic mechanisms mediating default but also inducible homeostatic maintenance of firing behavior of dentate granule cells. If one set of protective mechanisms was impaired, the other set would compensate and keep the gate intact.Degeneracy of synaptic and intrinsic properties is directly relevant in the context of epilepsy. For example, degenerate synaptic and intrinsic properties are important for the spatially and temporally sparse firing of dentate granule cells117. It is well established that even strong excitatory input from the entorhinal cortex leads only to limited activity in dentate granule cells. Their relative inertia to perforant path input is partly due to specific intrinsic biophysical properties such as hyperpolarized resting potential, spike rate adaptation and a low expression of active channels in dendrites118. Moreover, dentate granule cells have been reported to upregulate their leak  and HCN channels  and thereby further decrease their excitability in temporal lobe epilepsy (TLE)123. This can be seen as an antiepileptic compensatory reaction36 to proepileptic changes such as the enhancement of main excitatory perforant path synapses of dentate granule cells124. This suggests that a compensatory recruitment of three different ion channels can support robust maintenance of firing rate homeostasis, which would otherwise be impaired by synaptic pathology in epileptic tissue. This might partially explain the robustness of dentate granule cells against excitotoxic cell death in hippocampal sclerosis, which is associated with TLE36. Intriguingly, ion channels that get upregulated in dentate granule cells in epilepsy might be suitable candidates for pharmacological or genetic antiepileptic treatment125.There exists ample experimental evidence for degenerate intrinsic and synaptic mechanisms to protect the dentate gate126. Moreover, even synaptic inhibition itself is supported by structurally diverse mechanisms. Specifically, the existence of a stunning diversity in GABAergic interneurons of the dentate gyrus131 suggests significant degeneracy in maintaining synaptic dendritic and somatic inhibition controlling the recruitment of dentate granule cells132. And if, despite its degeneracy and robustness, synaptic inhibition becomes impaired, tonic extrasynaptic inhibition can still provide some protection. The evidence shows namely that extrasynaptic inhibition remains preserved or even becomes enhanced in some animal models of epilepsy134. Hence, the increase in extrasynaptic inhibition in case of impaired synaptic inhibition suggests that degenerate mechanisms protect the dentate gate at the network level.In addition to intrinsic channels, extrinsic network mechanisms also contribute to the protection of the dentate gate. For example synaptic, phasic as well as extrasynaptic, tonic GABAergic inhibition is known to be exceptionally strong in the dentate gyrus135 to traumatic brain injury (TBI) models136. Stereotypical changes in the dentate gyrus network in all these different animal models of TLE have been well characterized137. They include loss of mossy cells and hilar GABAergic neurons, sprouting of inhibitory synapses and changes in GABA currents and their reversal potentials, increased recurrent excitation (due to mossy fiber sprouting), enhanced adult neurogenesis and astrocytic gliosis140.Degenerate protection mechanisms allow for multiple routes to failure. Because multiple mechanisms protect the dentate gate, there are different ways to make it fail. This is reflected in the variety of animal models of epilepsy, ranging from kindling or status-epilepticus models induced by pilocarpine, kainate or electrical stimulation136 in contrast to intrahippocampal kainate injection models121. Also changes in dendritic and somatic GABAergic synaptic inhibition are complex and difficult to interpret139. This is further complicated by depolarizing shifts in GABA reversal potentials caused by chloride dysregulation, reviewed in ref. 141. We believe that future research guided by the degeneracy framework might help reconcile some controversies regarding seemingly conflicting findings of intact142, reduced144, enhanced145 or first reduced and later enhanced146 GABAergic inhibition in TLE. The concept of degeneracy could help elucidate how changes in inhibition in early and later stages of epileptogenesis interact with changes in excitation (including mossy fibre sprouting), cell loss and neurogenesis. The challenge is to determine, which of these changes are adaptive or maladaptive117.However, despite similarities between distinct animal models of TLE, there are also differences that are still not well understood. For example, intrinsic properties of granule cells are largely unaltered in TBI models136. Interestingly, this picture seems to include degeneracy at the molecular, cellular and network levels. For example, convergent mTOR, TLR4 and VEGF receptor signaling has been found to be involved in synaptic changes, that is, enhanced excitatory AMPA currents, altered inhibition, chloride pump changes and mossy fiber sprouting, as well as in cellular changes, that is, cell loss, neurogenesis and astrogliosis . At the network level, these synaptic and cellular changes drive jointly dentate gate disruption and contribute to epileptogenesis136. The details still need to be clarified but multiscale network models of the dentate gyrus emerge as a promising tool to reveal the conditions and limits under which these synaptic and cellular changes are adaptive or maladaptive150. Their combination with multiscale experimental approaches will help resolve controversies concerning the question to what extent do altered excitation124 and inhibition139, neurogenesis152, mossy fiber sprouting155 or mossy cell loss158 contribute to dentate hyperexcitability and epileptogenesis.In early epileptogenesis induced by TBI (first days to weeks upon injury), an integrated picture starts emerging for synaptic and cellular changes in the dentate circuitry162; but see also a surprising robustness of CA1 pyramidal cells in ref. 163. However, in line with the concept of multiple degenerate routes toward epilepsy, the Dravet-like phenotype can also result from enhanced excitability of excitatory neurons165 or enhanced synaptic excitation166 in spite of mostly intact GABAergic inhibition.The framework of degeneracy may help reconcile the ‘impaired inhibition’ with the ‘enhanced excitation’ hypotheses not only in TLE but also for example in Dravet syndrome. A Dravet-like epileptic phenotype can arise as a consequence of a Nav1.1 sodium channel deletion in GABAergic interneurons. Such an interneuron-specific Nav1.1 deletion reduces GABAergic inhibition due to impaired firing of GABAergic interneurons and is sufficient to cause Dravet-like seizures59. In patients with deficient sodium channels in GABAergic inhibitory neurons, a pharmacological block of sodium channels would be ineffective or even counterproductive167, whereas in patients with hyperactive sodium channels in excitatory neurons it may be an effective therapy. Indeed, clinicians usually avoid giving sodium channel blockers to Dravet patients with a loss of function mutation in the SCN1A sodium channel subunit. This is also the case for those with a loss-of-function mutation in the SCN2A subunit, whereas patients with a gain-of-function mutation in the SCN2A subunit usually benefit greatly from sodium channel blockers169; see also ref. 59 for the cell type dependence of the loss/gain-of-function concepts. Similarly, in TLE patients with chloride dysregulation, leading to excitatory GABA reversal potentials, enhancement of GABAergic signaling  might worsen rather then suppress seizures, despite pathologically diminished GABA-A conductances170, see also ref. 171. Thus, by drawing our attention to multiple causal links and their context, degeneracy can account for therapy failures and suggest new therapy approaches.Consequently, the efficiency of personalized therapy for Dravet syndrome may depend to some extent on the underlying circuit changes, which may be cell type specificGABAergic initiation hypothesis has recently been proposed172 to account for increased interneuronal activity prior to seizure onset175. This is an example of another potential route to seizures outside the typical context of excitation-inhibition imbalance. It also illustrates that although hyperexcitability of principal neurons may be a key feature of seizure-prone circuits, it is not the only pathological change leading to seizures and epilepsy. As noted above, individual excitatory neurons may not be hyperexcitable as judged from their FI curves68 and population responses may be preceded by strong inhibition. Thus, single-neuron hyperexcitability should be distinguished from circuit hyperexcitability underlying seizures. Nevertheless, on average, excitatory and inhibitory cell activity is higher during a seizure than in the interictal state175.Degeneracy may help to explain counter-intuitive observations about inhibition and excitation not only in epileptogenesis, but also in ictogenesis. For example, a 178. These dynamotypes, composed as a combination of 4 onset and 4 offset bifurcations, characterise seizure dynamics based on measurable local field potentials, with certain dynamotypes occurring more frequently and some occurring in combination178. The existence of multiple dynamotypes is a prime example of the degenerate nature of seizure dynamics.There is an astounding variety of causes and features of epileptic seizures. However, surprisingly, computational analysis has revealed that seizure dynamics display certain invariant properties. Dynamical systems analysis of transitions occurring at seizure onset and offset showed that most seizures can be classified into one of 16 dynamotypes176. A combination of experiments and dynamical modelling in the study by Jirsa et al.176 revealed that seizure dynamics share general fundamental properties179, described in more detail below. However, this does not mean that biophysical mechanisms of seizure generation are identical across distinct brain regions and species. On the contrary, it is likely that multiple different molecular, cellular and circuit mechanisms are capable of generating the observed seizure dynamics. Therefore, the authors have proposed that “there exists a wide array of possible biophysical mechanisms for seizure genesis, while preserving central invariant properties”176. This proposal is in agreement with the concept of degeneracy in epilepsy.Unexpectedly, similar dynamics were found in different brain regions and in three different species including human, zebrafish and mouse176, for a critical discussion see ref. 180. A slow variable, the permittivity variable181, determines the emergence of seizure onsets and offsets. Several different biophysical mechanisms could underlie this slow variable such as accumulation of extracellular potassium184 or changes in energy metabolism176. Jirsa et al.176 experimentally showed that potassium accumulation and metabolic changes (oxygen and ATP consumption) were indeed correlated with the slow onset of seizure-like events. However, other slow processes, operating on a similar time scale, e.g. short-term synaptic depression185 or concentration changes of other ion species such as chloride184 might also contribute to the biophysical implementation of the slow permittivity variable.The corresponding dynamical model, called Epileptor, captures invariant dynamical properties of seizure events using only five state variables176. Nevertheless, they showed in their own experiments that invariant dynamics of seizure-like events remain preserved even after dramatic changes of conditions such as disrupting synaptic release. This is another example showing that the Epileptor state variables, which underlie the invariant properties of simulated seizures, can be instantiated by different underlying physiological mechanisms. In agreement with this interpretation and fully in the spirit of degeneracy, the authors concluded that the above mentioned physiological correlates of the five state variables  “may be only valid for (…) very specific experimental conditions” and emphasized that many other parameter configurations and trajectories could lead to the conserved system dynamics and behaviour176, see also ref. 171).This is the case also for the remaining four faster variables. Based on electrophysiological recordings, the authors have linked the first state variable of the Epileptor to excitatory glutamatergic synaptic activity and the second state variable to inhibitory GABAergic activity194.An important example for degeneracy in epilepsy at the border between macro- and micro-circuit scales is related to extracellular electrical recordings, including local field potentials (LFP), electrocorticogram (ECoG), and electroencephalogram (EEG). These extracellular recordings constitute a crucial tool to discern physiological and pathological patterns of network activity at different spatial scales198. Together these imply that changes in LFP recordings are expected with epileptic disorders, which have indeed been shown across different brain regions207. Importantly, these observations also imply that the interpretations and analyses of extracellular recordings, their frequency-dependent properties, and spatial spread must account for pathological changes in ion channel distributions and input synchrony.With specific reference to LFPs, it is clear from the analyses above that epileptic disorders are associated with changes in ion channel densities and synchrony or correlation in activity patterns. LFP and its frequency-dependent characteristics are critically reliant on single-neuron properties and on input correlations210. For instance, although EEG can be macroscopically similar across different subjects, the firing patterns and the ion-channel compositions of the distinct neurons can still be very different. In addition, LFP oscillations in the theta frequency range, which are observed in the hippocampus during exploratory behavior, have been linked both to intrinsic intra-hippocampal activation216 as well as to the activation of several afferent areas including entorhinal cortex217 and the medial septal-diagonal band of Broca216. Similar observations have been reported about the differential origins of gamma oscillations as well219. Thus, physiological LFP oscillations might emerge due to intra-regional but also inter-regional circuit mechanisms.There are several lines of support for degeneracy in the generation of similar LFP and EEG patterns210.Degeneracy suggests that not only physiological patterns of activity such as theta and gamma oscillations but also pathological patterns might emerge due to multiple combinations of disparate mechanisms. For instance, hypersynchronous seizure-associated oscillations can arise from altered activity in several brain regions due to changes in disparate network components such as excitatory and inhibitory transmission or cell-specific intrinsic properties208. If validated in experiments, this would be an important lesson teaching us that “ostensibly similar epilepsy expression at the macroscopic scale can originate from a variety of mechanisms at the microscopic scale”208. In a similar vein, the authors of a recent study on “divergent paths to seizure-like events” concluded that “ostensibly similar pathological discharges can arise from different sources”171.Epileptologists are becoming increasingly aware of the fact that similar macroscopic activity  can be brought about by different underlying microscopic activities. As suggested in a recent review on micro-macro relationships in seizure networks, there are possible, although not yet experimentally shown, scenarios in which similar EEG in different patients could emerge from different activities of distinct hippocampal cell types220. Failure to recognize degeneracy or the manifestation of the many-to-one mappings between neural circuit components and extracellular recordings might result in negative side effects of drugs that are ineffectual as well220. Thus, analyses and interpretation of extracellular potentials must carefully account for the manifestation of considerable heterogeneity in the parametric space of neural circuits expressing degeneracy in the generation of these potentials. Basic research at the microcircuit and cellular scales is essential to elucidate the complex one-to-many mapping between similar electrographic recordings of seizures and distinct local network mechanisms220.The expression of such degeneracy, and the consequent macro-micro disconnect has critical implications for how extracellular recordings are interpreted and how therapeutic targets are designed220.Together, we emphasize the need to recognize degeneracy in the emergence of disrupted extracellular signatures associated with epilepsy and the divergent paths to similar seizure events. These observations caution against extrapolation of similarities in extracellular signatures at the macroscopic scale to imply similarities of sources and mechanisms at the microscopic scale, involving disparate combinations of cellular and synaptic componentsSimilarly to the network and single-cell levels, also at the systems level, many interacting components are known to contribute to the development of epilepsy. Here we highlight the immune system, the blood brain barrier and their interactions with neural circuits.221 but not in other222 animal models of epilepsy. This has led to controversies and questions whether seizures cause neuronal loss, and whether neuronal death is necessary and/or sufficient for triggering epileptogenesis223. Current evidence indicates that traumatic brain injury and associated neuronal death224 are capable of triggering epilepsy development in humans225 and model animals226. However, other experimental evidence suggests that epileptogenesis is possible also without apparent signs of neuronal loss when triggered by BBB breakdown222. Thus, neuronal loss seems sufficient but not necessary for triggering epileptogenesis. This can be understood by looking at epileptogenesis in the context of degeneracy.Data from clinical and animal model studies show that similar epilepsy phenotypes can be associated with distinct underlying neuronal and inflammatory mechanisms. For example, seizures are accompanied by neuronal death in some227 and its crosstalk to multiple processes in the central nervous system228. Recent studies emphasize the key role of the immune system in the development of epilepsy230. This is unsurprising given that nervous and innate immune systems have close developmental trajectories with extensive mechanistic overlap231.One origin of degeneracy in epileptogenesis Fig.  lies in 233. This cell type is involved not only in neuroinflammation, but also in inhibiting neuronal excitability in an activity-dependent fashion234. Furthermore, microglia regulate the secretion of, among others, IL-1 and TNF that are known to modulate neuronal excitability and seizure threshold236. Moreover, microglia are only one among a growing list of neuroimmunity-associated players involved in epileptogenesis.The interconnectedness of nervous and immune systems can be illustrated with functions of microglia, the major player of brain innate immunity237, neuronal activity235, neuronal loss223 and network reorganization 238. Additional complexity is introduced by the fact that neuroimmune responses can be triggered not only by neurological injury, but also by downstream pathological changes which are characteristic of epilepsy and the ictal activity itself. For instance, enhanced BBB permeability was shown to be induced by epileptic seizures240. And vice versa, the spillover of brain-born substances, following BBB leakage, can cause secondary neuroinflammation241. In this way, seizures may develop via multiple mechanisms including BBB disruption, neuroinflammation and/or neuronal loss and network remodelling  permeability242. We have described the neuro-immune crosstalk in the context of neurological injury using a dynamical systems approach. In agreement with experimental data from three animal models245, simulations showed that neuronal loss can be sufficient but is not necessary to drive epileptogenesis. Overall, computational modelling supports the concept that in the brain with its degenerate mechanisms, multiple different pathological mechanisms may contribute to epileptogenesis requiring different kinds of interventions for successful treatment242. However, there are still many unanswered questions related to cell loss. For example, the loss of certain interneuron subtypes246 and the associated reduced inhibition and epilepsy247 has not yet been fully understood and compared with the loss of principal neurons in the context of epileptogenesis.We have recently created a phenomenological model of these major epileptogenic processes and their interactions at realistic time scales Fig. 242. We h248. Creating models of neural circuits that can bridge two or more scales is a challenging task because of the nested hierarchy of molecular, cellular and supracellular networks with many feedforward and feedback loops between the scales. However, in well studied systems, multiscale models can provide new insights, which are relevant for epilepsy in the context of degeneracy.Degeneracy is a multiscale phenomenon present at multiple levels of brain structure. Degeneracy implies that different processes on a lower level can lead to a certain phenomenon on a higher level. If phenomena on different scales interact, multiscale modelling becomes necessary. Therefore, deeper understanding of degenerate excitable systems requires multiscale computational approaches249 is an intriguing example of multiscale modelling connecting the ion channel, cellular and microcircuit scales. The model showed that enhancing T-type calcium channel activation or reducing inhibitory GABA-A synaptic channel activation—in isolation as well as in combination—converted physiological network activity to seizure-like discharges. The results were in agreement with clinical observations of multiple different mutations in GABA-A receptors and T-type calcium channels in human patients and animals. The model predicted that these different mutations can lead to the same phenotype of absence epilepsy. In this way, the simulations have linked individual genetic variability in patients, simulated as the variability in the parameters of GABA-A and T-type calcium channels, to childhood absence epilepsy. Moreover, the model suggested plausible explanations for the failure or success of pharmacological medications targeting GABA-A and/or T-type calcium channels. Importantly, modelling predicted the necessity of multitarget therapy, simultaneously enhancing GABA-A transmission and suppressing T-type calcium channel activation, for patients with mutations in both ion channels  or its model is said to be Pareto optimal if there is no other phenotype/model that improves any of its biological objectives without worsening at least one other objective257. Pareto optimality for the trade-off between energy efficiency and functional effectiveness has been suggested as a guiding principle for modelling neurons and neural circuits259 and for reducing their degenerate parameter space (including ion channel space) to low-dimensional manifolds259. Hence Pareto theory might be used to improve population modelling of healthy but also epileptic neurons and neuronal circuits.In degenerate systems, instead of a single model, a large population of models with different parameter combinations is able to generate similar behavior. Consequently, in addition to multiscale modelling, degeneracy requires population modelling of neurons and neural circuits260, see Fig. 261. The authors called such hypothetical medicaments that optimally modulate multiple targets holistic virtual drugs. A similar approach could be adopted in epilepsy research for finding therapeutically efficient sets of perturbations of multiple ion channels that would switch hyperexcitable neuronal phenotypes to control phenotypes with normal excitability.The upside of using populations of  models is the ability to predict novel multicausal treatment options. Currently many computer models of epilepsy treatment simulate only monocausal pharmacological effects on one type of ion channels. Using populations of conductance-based models of neurons and their circuits, implementing synaptic and intrinsic channel variability would enable predictions for a combination of multiple therapeutic targets, that is, multitarget therapy, in silico. The use of such population-based in silico models could contribute to the discovery of new antiepileptic multitarget drug cocktails262 and distinct h-channel kinetics and expression265. In addition, dendrites of human pyramidal cells show complex calcium-mediated action potentials266, a high threshold for NMDA spikes267 and faster backpropagation of action potentials as well as forward propagation of excitatory postsynaptic potentials268. The uniqueness or generality of these recently characterized properties of human neurons with respect to their animal counterparts needs to be investigated in more detail270. Nevertheless, it is plausible to assume that the cell-to-cell variability and degeneracy discovered in animal neurons21 is also present in human neurons and their circuits.Recent studies of human neurons and neural circuits have begun to reveal unique properties of the human brain at the cell and circuit level. For example, human pyramidal neurons appear to exhibit enhanced dendritic compartmentalisation265, see also ref. 271, might be linked to the degeneracy of electrical resonance properties20 that are potentially important for theta oscillations in the cortex265. The influence of a change in HCN channel expression or kinetics on network excitability is complex due to the intricate role that HCN-mediated current (Ih) displays within a neuron272, on the one hand depolarizing resting membrane potential273, on the other hand decreasing input resistance and selectively diminishing dendritic excitability274. Degeneracy implies that the effects of ion channel changes may depend on the context, namely by the properties of other intrinsic and synaptic mechanisms. Therefore, compensatory or maladaptive changes in other mechanisms might explain why both loss-of-function as well as gain-of-function in Ih can lead to epilepsy275.For instance, the diversity in human h-channels (HCN channels)276. Combined with populations of realistic cell models and network modelling, this work has provided a first step towards a better understanding of morphological and ion channel changes associated with hyperexcitability of the dentate gyrus circuitry.Epilepsy research has begun to benefit from the increased availability of living human brain samples. Transcriptomic, morphological and electrophysiological data from resected human epileptic tissue started providing insights into the complex interplay between altered ion channels and morphological changes. In a recent study, such human multimodal data were obtained from living hippocampal granule cells260  The source of hyperexcitability could manifest animal-to-animal and circuit-to-circuit variability, thus precluding the targeting of individual ion-channels or receptors across all animals and circuits. (ii) As hyperexcitability could emerge through disparate routes, it is equally possible that reversal of hyperexcitability could be achieved through disparate routes260 Fig. . The use6. In addition, a degenerate nervous system sometimes displays compensatory adaptations, which undermine therapeutic interventions focusing on a single target92. Therefore, multitarget strategies in pharmacology or in neuromodulatory stimulation might be more promising than monotarget strategies . In fact, many already approved antiseizure drugs affect multiple targets278. Degeneracy offers rationale also for another currently considered option of multitarget pharmacology, namely using combinations of drugs with different single targets instead of single multitarget drugs278 or even using combinations of multitarget drugs. However, an intense basic and clinical research is still needed to find drug combinations with synergistic (supraadditive) therapeutic effects and low (infraadditive) toxicity281. Similarly, future clinical research is needed to provide evidence for beneficial effects of neurostimulation targeting multiple brain areas. Such evidence is currently sparse282.The recognition of degeneracy in epileptic pathology could enable simultaneous use of multiple disparate components and routes to reverse hyperexcitability. Hence there is no need for sticking to one specific drug target. In fact, to repair a failed degenerate system, it is often not enough to restore a single target mechanism Fig. . One rea109.As there are many potential drug targets, the choice of specific drugs could be allowed to take advantage of circuit-specific differences in target expression profiles. For instance, if hyperexcitability is specific to a neuronal subtype in a given brain region, this could be reversed by identifying mechanisms that are abundant in that neuronal subtype but not others. However, due to degeneracy, it is sometimes impossible to determine which neuron subtype or ion channel subtype is more crucial than others since it might depend on other, e.g., synaptic parameters6. In other words, reductionist monocausal research strategies focusing on isolated components are only partially suitable for studying complex degenerate systems283. Moreover, the conceptual framework of degeneracy with its emphasis on multitarget and multicausal thinking has consequences not only for therapy development but also for basic research and its perturbation and lesion strategies. For example, multitarget lesion experiments6 or multi-knockout studies might be necessary to evoke dysfunction in degenerate neural or molecular networks. Measuring and perturbing multiple parameters and mechanisms simultaneously is challenging but can be facilitated by computational approaches such as multiscale and population modelling (see above).Degeneracy of the brain creates opportunities but also challenges for precision or personalized medicine, which tries to develop therapies targeted to the specific etiology and pathophysiology of individual patients. One challenge in basic and clinical research of degeneracy is measuring multiple hyperexcitability-relevant parameters in the same individual . Ideally, in a denegerate circuit, one would need to know most or all contributing components/mechanisms of hyperexcitability including the knowledge of most relevant hub mechanisms with highest “cruciality score” of their involvementHow is it possible that degeneracy makes the excitability of neural circuits robust and yet susceptible to epilepsy? We would like to argue that the evolution of the complex nervous system has led to the emergence of multiple protective mechanisms against the hyperexcitability of neural circuits but at the same time to multiple potential pathways towards the failure of this protection. In a healthy state, multiple compensatory mechanisms may act jointly with the potential to compensate for each other’s failure, thereby supporting the robustness of physiological neural excitability. The compensation may be immediate (“default” or “constitutive” compensation) or it can be recruited on demand with a time delay as a form of “inducible” homeostatic plasticity (“homeostatic compensation”).284 and elsewhere287. The authors of visual cortex studies have explicitly stated that “multiple, partially redundant forms of homeostatic plasticity may ensure that network compensation can be achieved in response to a wide range of sensory perturbations”284. As we mentioned before, partial redundancy is a term that is sometimes used in the literature instead of degeneracy. We believe that similar research in the context of epilepsy will reveal degeneracy in homeostatic plasticity mechanisms protecting the hippocampus and other brain regions against hyperexcitability and epileptogenesis. Support for this idea comes also from computational models288 and control theory289, which indicate that degenerate homeostatic mechanisms provide functional benefits. For example, an effective control of neuronal firing rate, including both its mean and variance, can be achieved through the degeneracy of cooperative synaptic and intrinsic homeostatic plasticity289.Notably, degeneracy in homeostatic plasticity mechanisms has been demonstrated in visual cortex290. The greater the number of interacting mechanisms, the more complex, flexible and robust the system becomes. At the same time, the higher are also the system’s energy costs linked to the extent of functional redundancy of identical components6. Since energy and material resources are limited, complex biological organisms display universal trade-offs between (1) functional performance, its (2) robustness and (3) flexibility and (4) energy costs291. Degeneracy facilitates the robustness and flexibility of functional behavior13. In contrast, pure redundancy increases the energy costs6. Through degeneracy evolution seems to have optimized biological systems for these multi-objective trade-offs257. A biological system tries to maximize functionality, flexibility and robustness but minimize energy expenditure293. Therefore, it is plausible that degenerate living systems evolved to become Pareto optimal for these multiple objectives. Thus, one would expect biological systems, including nervous systems295, to exist close to an optimal compromise between low energy costs and high functionality . In line with these ideas, one recent study proposed that “degeneracy affords a flexibility that offsets the cost of redundancy”296. Another recent work indicated that heterogeneity of synaptic parameters decreases the number of synapses needed for the processing of visual inputs, resulting in a cost benefit297. And, intriguingly, the results of Yang et al.295 suggested that the achievement of multiple biological goals (such as specific firing rates and energy efficiency) may only be possible with a sufficiently large diversity of interacting mechanisms .Degeneracy in biological systems is closely linked to their complexity in terms of the number of mutually interacting individual components and mechanisms299. That would open the possibility for every mechanism being expressed at the lower (and hence cheaper) end of its dynamical range299. In this way, the function  would be preserved at a lower cost of its protection. Currently such optimal cost sharing is only a hypothesis that needs to be tested in experiments and simulations. On the other hand, it is also possible that the relatively high vulnerability of the nervous system with respect to hyperexcitability is a high evolutionary price that we have to pay for the enormous computational capabilities of our energy-efficient brains293, which seem to operate close to criticality that maximises information-processing300, but see also ref. 301.The conceptual link between degeneracy and evolutionary optimization opens many interesting questions. For example, counterintuitively, expressing multiple complementary protective mechanisms may paradoxically help reduce the overall cost of protection. This could be the case if activation of multiple protective mechanisms allows for optimal cost sharing among them299. Brain injuries  may shift the balance and energy expenditure towards immune defense302. Future research may clarify whether epileptogenesis can be understood as a consequence of chronically enhanced immune defence  at the expense of suppressed excitability homeostasis.Another largely unexplored area is the potential trade-off between immune defense and homeostasis of neural excitability. Immune defense of the brain is costly and under threatening conditions it might get activated at the expense of neural homeostasisDeveloping effective treatments for epilepsy remains a challenge. The complex and multifaceted nature of this disease continues to fuel controversies about its origins. In this perspective article, we argued that conflicting hypotheses could be reconciled by considering the degeneracy of the brain, which manifests itself in multiple routes leading to similar function or dysfunction. We exemplified degeneracy at three different levels, ranging from the cellular to the network and systems level. First, at the cellular level, we described the relevance of ion channel degeneracy for epilepsy and discussed its interplay with dendritic morphology. Second, at the network level, we provided examples of degenerate synaptic and intrinsic neuronal properties which support the robustness of neuronal networks but may also lead to diverse responses upon ictogenic and epileptogenic perturbations. Third, at the system level, we provided examples for degeneracy in the intricate interactions between the immune and nervous systems. Finally, we showed that computational approaches including multiscale and so called population (or ensemble/database) models of neurons and neural circuits might help disentangle the complex web of physiological and pathological adaptations. Such models may contribute to identifying the best personalized multitarget strategies for directing the system towards a physiological state.Further information on research design is available in the Peer Review FileDescription of Additional Supplementary FilesSupplementary Data 1Reporting Summary


New physiologic findings related to sodium homeostasis and pathophysiologic associations require a new vision for sodium, fluid and blood pressure management in dialysis-dependent chronic kidney disease patients. The traditional dry weight probing approach that has prevailed for many years must be reviewed in light of these findings and enriched by availability of new tools for monitoring and handling sodium and water imbalances. A comprehensive and integrated approach is needed to improve further cardiac health in hemodialysis (HD) patients. Adequate management of sodium, water, volume and hemodynamic control of HD patients relies on a stepwise approach: the first entails assessment and monitoring of fluid status and relies on clinical judgement supported by specific tools that are online embedded in the HD machine or devices used offline; the second consists of acting on correcting fluid imbalance mainly through dialysis prescription  but also on guidance related to diet and thirst management; the third consist of fine tuning treatment prescription to patient responses and tolerance with the support of innovative tools such as artificial intelligence and remote pervasive health trackers. It is time to come back to sodium and water imbalance as the root cause of the problem and not to act primarily on their consequences  or organ damage . We know the problem and have the tools to assess and manage in a more precise way sodium and fluid in HD patients. We strongly call for a sodium first approach to reduce disease burden and improve cardiac health in dialysis-dependent chronic kidney disease patients. Despite recent improvements in dialysis patient outcomes –3, cardiFindings of recent studies may be taken as examples to highlight the burden of this problem. Fluid overload is quite common in hemodialysis patients. In a large cohort of incident hemodialysis patients >40.000), moderate fluid overload >2.5 l) assessed by multifrequency bioimpedance was noted in 46% of patients, while a more severe one (>6 l) was observed in about 10%  and losses  in which kidney function and neuroendocrine factors play a major role. Traditionally, total body sodium (TBS) distributed in the extracellular volume (ECV) and bone, was thought to remain relatively constant over time and adjusted to intake changes. This fine regulation of TBS depends on kidney function and blood pressure as described in a kidney-centric model elaborated by Guyton et al . Accordi factors –48. Phag factors . This meechanism . This inechanism , 51. In echanism . All theechanism .In anuric chronic kidney disease dialysis patients, sodium and water balance rely mainly on renal replacement treatment schedule, dietary intake and likely on skin, gut, lungs and oxidative process. Conventional, short and intermittent hemodialysis treatment schedules create cyclic fluctuation alternating between a slow loading phase  and a fast-unloading phase , making fluid and volume management quite challenging , 29. As Impairment of the sodium metabolism in patients with ESRD often results from longstanding pathologic processes that start early with kidney disease and aggravates steadily over time with progredient loss of kidney function. Sodium imbalance reflects the inability of the diseased kidney to handle daily sodium and water load.Sodium accumulation in the extracellular space is the most common and diagnosable consequence of sodium imbalance in CKD patients. This refers to sodium in the extracellular fluid volume, the so called osmotically active sodium, which tends to increase thirst with subsequent expansion of the extracellular volume in the circulation and the interstitial space. Edema, hypervolemia, hypertension and congestive heart failure are among the most common manifestations of sodium accumulation and fluid overload translating into consequent cardiac and vascular damages. This pathophysiological dynamic has rendered chronic fluid overload with or without hypertension to be recognized as one of the main causes of morbidity in CKD patients. However, as summarized in recent reviews, next to sequelae on fluid and hemodynamics, sodium imbalance also associates with multiple end organ damages including cardiac remodeling (left ventricular hypertrophy), proarrhythmic condition, white matter brain damage, atherosclerotic lesion, protein energy wasting, inflammation and lung disorder with pulmonary hypertension , 55.On the other hand, predialysis hyponatremia, reflecting hypotonicity and sodium-free water excess, is observed in 10 to 15% HD patients . HyponatSodium accumulation in tissue, as discussed in the previous paragraph, also associates with chronic kidney disease progression. As documented through functional Na MRI imThe unphysiological profile of intermittent HD is recognized as a leading cause of dialysis intolerance and multiorgan morbidity , 66. ThiThe HD cyclic phenomenon may refer to a tide phenomenon with two phases of loading  and unloading  as described in more details below , 35, 67.During the interdialytic period, anuric HD patients tend to accumulate sodium and fluid according to fluid and dietary intake, leading to chronic fluid overload. In this condition, fluid overload has two consequences: the first is marked by weight gain and progressive increase of systemic arterial pressure and pulmonary arterial pressure with cardiac stretching during the interdialytic phase; the second reflects fluid accumulation and translates into cardiac stretching and structural cardiac remodeling .During the intradialytic period, sodium and fluid are removed mainly through ultrafiltration  and negative dialysate-to-plasma sodium gradient. Volume depletion leads to hypovolemia that triggers adaptative hemodynamic response to preserve arterial pressure. To face hypovolemia and cardiac stroke reduction, hemodynamic stability (blood pressure and tissue perfusion) tends to be preserved by increasing vascular tone, mainly through vasoconstriction of alpha-adrenoceptor territories, and increase vascular refilling including venous return. Hemodynamic response and full adaptive response may be limited by critical hypovolemia  or cardiac impairment  or vascular refilling capacity . Recent functional dialytic imaging studies have shown that reductions in myocardial perfusion and contractility  are directly linked to ultrafiltration rate –72. In aWhatever the exact pathophysiologic consequences of this phenomenon, volemic changes (hyper- and hypo-volemia) provoke rapid alternating cycles of cardiac loading and unloading but still maintaining overtime an abnormal high pulmonary pressure level , 77. SucAdequate management of sodium, water, volume and hemodynamic control of hemodialysis patients relies on a stepwise approach , 67, 80:Sodium and fluid balance assessment and monitoring in HD patients is not an easy task . HoweverClinical management is currently summarized in the dry weight probing approach –84. The Non-invasive technology-based tools have been shown helpful to assess volemia, fluid status, or hemodynamic indicators .Inferior vena cava diameter (IVCD) and collapsibility index have been proposed to monitor intravascular volume and right atrial pressure or central venous pressure changes in dialysis patients with positive outcomes . HoweverRelative blood volume change (RBV) and refilling rate capacity during dialysis assessed by online blood volume sensor embedded in HD machines has been also proposed to guide fluid management , 95. In Bioimpedance has been proposed over the last few years as a more precise way to assess fluid status in dialysis patients , 102. SeEchocardiography is a reliable tool in expert hands to monitor cardiac impact of fluid depletion both on functional and morphological aspects –108. It Regional chest bioimpedance cardiographic device (NICaS), a non-invasive device, has been recently introduced to assess patient’s hemodynamic response to ultrafiltration . The devpost-hoc analysis for recurrent episodes of decompensated heart failure (HR 0.37) and cardiovascular events (HR 0.63) showed a significant risk reduction in the active arm. In hemodialysis patients with high cardiovascular risk, fluid management guided by lung ultrasound may help to reduce lung congestion more effectively than usual clinical care (Lung ultrasound has been proposed more recently to track silent fluid accumulation in the lung Interstitium (extravascular edema) reflecting both volume overload and cardiac dysfuntion , 112. Incal care .Cardiac biomarkers have been extensively explored in hemodialysis patients to disentangle fluid status and cardiac function or remodeling . Atrial via local or remote tissue organ damage. Consequences such as left ventricular hypertrophy and vascular stiffness positively associate with the amount of tissue sodium stored and may ultimately increase the risk of cardiac failure. In addition, sodium tissue accumulation contributes to metabolic and inflammatory disorders that enhance cardiovascular risk. In recent study assessing tissue sodium  by (Quantification of sodium accumulated in the tissue (skin and muscle) using sodium MRIs in dscle) by Na MRI inscle) by . A reducscle) by MRI remaiscle) by .New remote technology, so called ihealth trackers, offer convenient and interesting tools for monitoring in a fully automated and non-obstructive mode, HD patients during the interdialytic period . Long-teDry weight clinical management must be conceived as the overarching workflow aiming to ensure optimal fluid and hemodynamic management in dialysis patients , 129. ThReduce dietary salt intake is associated with clinical benefits, better cardiac outcomes in chronic kidney disease and hemodialysis patients. Adherence to a low-sodium diet is challenging but well established as crucial element for treatment success . Salt diReducing ultrafiltration rate is obviously the most logical approach to reduce cardiac morbidity in HD patients , 134. AgModulating a patient’s hemodynamic response through various tools embedded in HD machines is an appealing approach to maintain hemodynamic stability . MonitorAdjusting dialysis thermal balance to preserve peripheral vascular resistance and cardiac output is also a simple strategy to improve hemodynamic tolerance and reduce organ damage that has been proven clinically effective including systematic literature review , 146. InOptimizing sodium and water imbalance by means of hemodialysis is crucial to restore fluid and tonicity homeostasis , 149. ThBig data and artificial intelligence have already been successfully applied at the point of care to support physicians in the decision-making process. Availability of accurate, longitudinal, data set is a key factor for the development of reproducible predictive algorithms. In that setting, artificial intelligence relying on machine learning, neuronal network and deep learning, can be used to predict on an individualized, session-based, patient hemodynamic response  to dialysis-related prescriptions  on multiple relevant hemodynamic and dialysis adequacy parameters . Based oAdditional specific actions may be further required in cardiac compromised patients or to satisfy specific patient’s needs . It is nIn brief, indications of these medications and/or cardiac intervention should remain in the hand of cardiologists. At this stage, our point is to emphasize the fact that sodium, water and fluid imbalance should be the first line of action in HD patients. Medications and cardiac interventions are likely to be useful but should remain as second line of action and nevertheless used in combination with optimized sodium and water management.A comprehensive and integrated approach is needed to improve further cardiac outcome in HD patients. From clinical research, it is obvious that none of the tool described earlier used alone has the capacity to address issues raised by sodium, water and fluid imbalance. Future research should address this challenge by associating different levels of action as briefly schematized in As delineated in this comprehensive essay, new findings related to sodium homeostasis and pathophysiologic links require a new vision for sodium, fluid and pressure management in dialysis dependent chronic kidney disease patients. The traditional dry weight probing approach that has prevailed for many years must be reviewed in the light of these new findings and enriched by availability of new tools for monitoring and handling sodium and water imbalance. It is time to come back to sodium and water imbalance as cause root of the problem and not to act on their consequences  or organ damage . We know the problem and have the tools to assess and manage in a more precise way sodium and fluid disorders in hemodialysis patients. We strongly call for a sodium first approach to reduce disease burden and improve cardiac health in chronic kidney disease patients.All authors listed have made a substantial, direct, and intellectual contribution to the work, and approved it for publication.Authors AM and BC were employed by company Fresenius Medical Care (FMC).The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Climate change increases both the intensity and frequency of environmental stresses such as temperature extremes, drought, and salinity. However, the majority of crop plants are sensitive to these stresses and huge yield penalties occur when they are exposed to these sub-optimal conditions. Crop plants cannot grow in natural environments where the abiotic stresses are extreme such as deserts, saline and high metal soils, Arctic and Antarctic regions, etc. In contrast, the extremophile plants or extremophytes, including halophytes , xerophytes (growing in dry and arid environments), resurrection plants , metal hyperaccumulators , etc. have evolved to complete their life cycles in these marginal habitats and have developed various mechanisms to cope with these stresses at anatomical, physiological, biochemical, and molecular levels. It is thus important to understand these mechanisms in extremophiles and to use that knowledge in the improvement of stress tolerance-related traits in cultivated crops to maximize the land area for the crop cultivation. In fact, in the past few decades, especially after the development of NGS technologies, plant scientists have shown a great interest in understanding the molecular genetic background of tolerance mechanisms in these astonishing plants and in transferring this knowledge to cultivated crops. This is especially feasible in the case of crop species which are closely related to an extremophile(s). Despite these efforts, the research in this area is in its infancy and the current knowledge is not enough, which warrants more studies on the extremophiles.In this regard, this Research Topic aimed to collect studies related to deciphering stress tolerance mechanisms in extremophiles that have the potential to be used in the improvement of crop stress tolerance for safeguarding yield. Studies related to understanding novel tolerance mechanisms of extremophiles are of special importance since they form the fundamental knowledge required for crop improvement.Guo et al. used genomic and transcriptomic strategies to understand the regulation of gene expression during salinity in model halophyte Puccinellia tenuiflora (Poaceae) and compared its response with several glycophytic Poaceae plants. This study unveiled the evolutionary network of salinity tolerance genes in P. tenuiflora and found that potassium channel and transporter gene families of P. tenuiflora were positively selected during evolution which cause higher K content under salinity stress.Halophytes evolved to survive under extreme saline conditions and some even require saline conditions for their normal metabolic function. Comparative studies between halophytes and glycophytes  are widely conducted in recent years to reveal how halophytes tolerate extreme conditions. Tamarix ramosissima (Tamaricaceae) is naturally widespread in harsh environments including shelterbelt forests which are important to reduce desertification in arid regions. It is a perennial shrub and its survival strategy under harsh conditions in its habitat are unknown. In such areas, precipitation is very low which requires the evolution of unique water use strategies for plants to growth and survive. Liu et al. measured the stem sap flow (SSF) of T. ramosissima daily during growth season to understand the water use strategies and found that SSF highly depends on water availability. It was found that T. ramosissima mainly uses deep soil water and ground water under extreme water-limiting environment, and that photosynthetic active radiation, air temperature and vapor pressure deficit are the main environmental drivers for its SSF under these severe conditions.Wang et al. surveyed TE compositions of two mangrove Sonnertia species, viz. salt tolerant S. alba (Lythraceae) and less tolerant relative S. caseolaris (Lythraceae). By using different approaches such as phylogenic analysis of long terminal repeat retrotransposons, small RNA sequencing and whole-genome bisulfite sequencing, the authors demonstrated that S. alba shows richer TEs than that of S. caseolaris. Also, S. alba exceptionally showed a burst in Gypsy retrotransposons, but this burst had a weak effect on the expressions of salt stress genes, suggesting that expansion of Gypsy retrotransposons is pervasive in mangroves which, however, is not correlated with salt-responsive gene expression in S. alba. Importantly, the study suggests that although TEs could be pervasively induced by stress, their co-option for the regulation of host genes should be cautious.Comparative studies between extremophiles and their stress sensitive crop relatives under stress conditions are also important ways to understand evolution of stress coping mechanisms. Plant genetic diversity for tolerance to harsh environments can also be evaluated through transposable element (TE) colonization. Cao et al. studied a unique halophyte, Suaeda aralocaspica (Amaranthaceae), that forms enlarged cotyledons. Under extreme salinity, this species of extremophiles postpones the development of true leaves and stays with cotyledons nearly for two months to avoid harmful effects of saline conditions on plant growth. Cao et al. performed in-depth investigation of cotyledon morphology and metabolism to shed light on the intriguing adaptation mechanism of this species. Contents of some metabolites, including osmolytes, and the expression of stress-related genes were markedly high under salinity. Moreover, this study demonstrated the developmental strategy of S. aralocaspica to improve homeostasis in energy consumption for enhancing early seedling performance under extreme levels of salt stress.Germination and early seedling growth are the key stages of plant life which are also sensitive to stress conditions. Nutrients are stored in cotyledons and resources required for establishment of photosynthetic machinery are provided by cotyledons in early development. Yan et al. studied the effects of salinity on the first steps of quinoa seed germination which is the imbibition stage. They used artificial NaCl and natural salt solutions for 8 h long imbibition and made transcriptomic and metabolomics analyses. Carbohydrate metabolism and antioxidant defense mechanisms were found to be regulating the seed initial imbibition during high salinity or under brackish water.Quinoa is a facultative halophyte with high nutritional value and is considered as a superfood that is attracting attention from consumers. Haloxylon aphyllum (Amaranthaceae) is a xero-halophyte which is dominant species in deserts of Iran. Excess dust exposure of this species negatively affects its growth and performance. In the last decade, studies on the beneficial effects of plant growth promoting bacteria (PGPB) on plant performance under stress conditions have significantly increased. Zilaie et al. applied two halotolerant plant growth promoting rhizobacteria to halophyte H. aphyllum and studies its response to salinity and to stress caused by dust coverage. Application of beneficial bacteria decreased the reactive oxygen species (ROS) accumulation and enhanced antioxidant capacity which led to more effective growth under desert conditions. Results from this study suggest that these PGPB not only confer the stress tolerance to the stress sensitive plant species but can also improve the thriving ability of extremophiles.Preventing desertification is a main goal for combatting adverse effects of climate change, and maintaining the natural desert-tolerant vegetation for those arid areas is an ambitious motive. Overall, the research studies highlighted in this editorial elucidate a few novel stress tolerance mechanisms in the extremophiles, which may have significant implications for plant biotechnology and crop improvement, especially for the development of stress-tolerant crop plants.All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.


Patients with hypertensive emergencies, malignant hypertension and acute severe hypertension are managed heterogeneously in clinical practice. Initiating anti-hypertensive therapy and setting BP goal in acute settings requires important considerations which differ slightly across various diagnoses and clinical contexts. This position paper by British and Irish Hypertension Society, aims to provide clinicians a framework for diagnosing, evaluating, and managing patients with hypertensive crisis, based on the critical appraisal of available evidence and expert opinion. High blood pressure (BP) is the most prevalent and important modifiable risk factor for cardiovascular disease and disability, worldwide . In 2015There is a lack of robust outcome data specifying BP targets, the speed of BP reduction and specific medications in patients with hypertensive crises . ManageAn extensive literature search using PubMed and Embase was undertaken using keywords see . RelevanVarious terminologies have been applied to describe severe elevation in BP, including acute severe hypertension, hypertensive urgency, hypertensive emergency, malignant hypertension (MHT), accelerated phase hypertension and hypertensive crisis. It is important to distinguish between the key terms to guide appropriate management and minimise the potential for iatrogenic harm.The definition of ‘severe’ has changed progressively in the last 70 years. Most experts would accept that a BP of >200/120 mmHg is severe, and needs urgent attention, but the degree of urgency depends on the precise circumstances. For example, a BP of 180/100 mmHg in a poorly adherent, uncontrolled chronically hypertensive patient, would not usually be considered as acute severe HTN needing immediate treatment, whereas a BP of 160/100 mmHg would be a medical (hypertensive) emergency in the context of acute end organ damage (EOD), such as preeclampsia. We prefer the term ‘acute severe hypertension’ to indicate patients with severe elevation in BP without evidence of acute and/or life-threatening EOD. Most patients presenting to emergency departments (ED) belong to this category and it is difficult to distinguish whether the rise in BP is acute or chronic especially if BP has not been measured recently. National Institute for Health and Care Excellence (NICE) guidelines (NG 136) refer to this subgroup as severe hypertension {NICE, 2019  –40 38–40Figure It is clear that there is a lack of robust clinical trial data and a lack of consensus over terminology and interpretation of the data available. Using BP levels as a threshold to determine if patients have a hypertensive emergency, and the use of terminologies like ‘hypertensive urgency’ dilute the strength of evidence. We suggest the development of established international standardised terminologies in this field.As a core concept, the pace of reduction in hypertensive emergencies is based on CPP, and there is an unmet need for developing user-friendly non-invasive methods of assessing cerebral flow in routine clinical settings. This might help develop individualised BP targets leading to a controlled MAP and CPP management.Less is known about underlying genetic, cultural, and environmental factors that predispose patients to hypertensive emergencies. Intrinsic heterogeneity in patients presenting with hypertensive crises and responses to therapy make RCTs difficult to design and follow through. To improve and develop an evidence base in this field prospective international observational studies either in the form of registries or trials need to be set up. These may not only help assess current treatment strategies but could also help develop biomarkers or a multivariate risk score system based on epidemiology, which in turn may help stratify patients adequately and enable personalised therapy. The set-up of a multi-national registry could also help identify areas with high prevalence rates of uncontrolled HTN and focus on regional trials to address knowledge gaps. Overall, any planned RCT should be pragmatic and relevant, and consider all the factors that are likely to affect the risks. Last but not the least, it is important to prevent nonadherence to medications right from the start i.e, at the point of diagnosis, by ensuring patients are at the centre of the shared decision-making. Throughout the patient’s journey perspectives change, and it is vital to continuously assess the factors that affect adherence both subjectively and objectively in a non-judgmental way, using the best available tools  within the clinical setting. Various strategies can be implemented including patient-focused solutions, using reminders/smart phone apps, regular follow-up, pill boxes and single combination pills. The ultimate goal of reducing the burden of cardiovascular disease resulting from uncontrolled hypertension is unattainable without patient partnership.Acute HTN management is heterogenous across various presentations, based on available resources and local expertise. High-quality evidence is either missing or where available does not necessarily conclusively favour specific rates of reduction in BP or specific medications. In conclusion, based on available evidence and where lacking consensus statements were made in consultation with the BIHS. The proposed set of recommendations for the management of acute hypertensive states aim to offer an evidence-based and consistent approach to the delivery of high-quality patient care.What is known about this topicManagement of hypertensive crisis varies across presentations and is based on available resources and local expertise.Heterogeneous terminologies used in the literature to categorize hypertensive crisis states pose challenges to the exact assessment of epidemiology and evidence synthesis.High-quality evidence is either missing or where available does not conclusively favour specific management strategies.What does this study addThis paper critically reviews the available evidence base including various guidelines available for the management of hypertensive crises.We propose to categorize hypertensive crisis into acute severe hypertension, malignant/ accelerated hypertension, and hypertensive emergencies based on pathophysiology.We provide a practical framework for the diagnosis and management of hypertensive crisis based on the available evidence and expert opinion, which can be adapted to specific clinical settings.Supplementary Text and Tables


Using odors to find food and mates is one of the most ancient and highly conserved behaviors. Arthropods from flies to moths to crabs use broadly similar strategies to navigate toward odor sources—such as integrating flow information with odor information, comparing odor concentration across sensors, and integrating odor information over time. Because arthropods share many homologous brain structures—antennal lobes for processing olfactory information, mechanosensors for processing flow, mushroom bodies (or hemi-ellipsoid bodies) for associative learning, and central complexes for navigation, it is likely that these closely related behaviors are mediated by conserved neural circuits. However, differences in the types of odors they seek, the physics of odor dispersal, and the physics of locomotion in water, air, and on substrates mean that these circuits must have adapted to generate a wide diversity of odor-seeking behaviors. In this review, we discuss common strategies and specializations observed in olfactory navigation behavior across arthropods, and review our current knowledge about the neural circuits subserving this behavior. We propose that a comparative study of arthropod nervous systems may provide insight into how a set of basic circuit structures has diversified to generate behavior adapted to different environments. Odor is a fundamental signal used to locate resources across the animal kingdom. Food sources, be they flowers, fruits, decaying corpses, or live humans, emit chemical signatures that can be transported long distances on wind or water currents and tracked back to their sources to find food. Like food, hospitable sites for egg laying also release chemical cues useful for localization. Finally, many animals release or deposit specific chemicals—pheromones—to enable conspecifics to find important locations in the environment. These include both volatile pheromones released to attract mates, and chemical trails that can be followed by conspecifics to a previously located food source.Arthropods—whether they’re ants at a picnic or mosquitoes on a summer evening—are famously good at tracking odors. Arthropoda is an enormous and varied phylum, with members found across even the most inhospitable environments. Behavioral studies across arthropod species have highlighted both common and divergent strategies in odor-seeking behavior. The arthropod brain has a highly conserved structure, with dedicated regions for processing odor and flow stimuli, learning temporal associations between scents and food rewards, and representing navigational variables to guide locomotion. However, the nature of the odors that arthropod species encounter and seek, the structure of the odor signals they follow, and the physical constraints of moving are highly variable across ecosystems, driving adaptive changes in sensation and locomotion. In this review, we highlight common features of olfactory navigation behavior that have been observed across arthropod species, and review current knowledge about the neural circuit structures that likely support these behaviors. We further describe key differences in behavior across species and speculate on possible changes in neural circuit structure and function that might underlie them. We argue that a comparative study of olfactory navigation behavior and circuitry across arthropods is likely to yield important insight into how nervous systems have diversified to adapt to different environments, and describe tools and resources that will be required to pursue this research program.2, a common insect cue released by prey, fermentation, and vegetation, is a volatile gas. In contrast, appetitive odorants for crustaceans are generally molecules like dissolved free amino acids, amines, nucleotides, and peptides, which are readily soluble in water, but not volatile . In this species, central neurons exhibit spatial tuning for locations along the antenna  is present. The dynamics required to elicit upwind progress can depend on odor as well as species. In flying A. aegypti mosquitoes, CO2 will only evoke strong upwind flight when presented as a filamentous plume, while skin odors can evoke the same behavior when presented as a broad, homogenous plume  and silk moths (B.mori) also exhibit cast-like turning upon loss of odor, but these casts are much more variable in their timing and structure than those of moths , rather than a bona fide navigation strategy. However, evidence from walking arthropods—insect and crustacean—suggests stopping plays an integral role in evidence accumulation Fig. d. CrawliThis survey of olfactory navigation behaviors suggests that a set of common high-level behaviors—surging, casting, and pausing—are evoked by different stimuli and stimulus dynamics across species. How might we understand these behavioral motifs as a product of the olfactory environments encountered by an animal? Weissburg  proposedNew tools for detailed, high throughput quantification of olfactory behaviors may allow scientists to test and expand on this intriguing hypothesis. In particular, the literature reviewed above suggests that animals adopt active strategies to increase their capacity to collect and integrate information about a plume. Modeling approaches suggest that insect-like searching behaviors arise as an optimal solution to navigating a turbulent plume through a Bayesian inference process  in the antennae Fig. a. ORNs eIn most arthropod olfactory systems, axons of ORNs that express the same receptor type converge on a smaller number of projection neurons (PNs) in structures known as glomeruli , odor information is carried to higher order olfactory areas by a variety of projection neurons (PNs). Uniglomerular PNs carry information from a single glomerulus—reflecting mostly input from one receptor type—while multi-glomerular PNs carry information from groups of glomeruli  is an associative structure implicated in olfactory learning. Many years of experiments support this role, starting from the observation that chemical ablation of the mushroom body abolishes learned odor aversion, but not innate aversion . Thought to perform innate olfactory processing, the lateral horn is a much more complex structure than the mushroom body, with 496 morphologically identified cell types in As described above, a key component of olfactory navigation in many species is the use of air or water-flow cues to provide a directional cue for navigation. In many terrestrial arthropods, such as flies  is a highly conserved region of the central complex and may play a role in setting navigational goals. The fan-shaped body receives two main types of inputs: columnar neurons (known as PFNs) and tangential neurons  has been observed in diverse arthropod lineages, including insects, crustaceans, chelicerates , onychophorans (velvet worms), and chilopods (centipedes) Homberg . While tA lateral accessory lobe or lateral complex is also found in many insect species  to determine which way to go when searching for an odor source, and move with a conserved set of high-level behavioral features . Second, arthropods rarely rely on a single sensory cue or strategy to find an odor source, but rather appear to be able to integrate many sources of information coherently. Finally, the arthropod brain is built on a scaffold of conserved structures , many of which have highly structured and conserved connectivity. How can the same brain scaffold be adapted to enable animals to effectively navigate toward odor goals in diverse environments, using diverse modes of locomotion? Given the ubiquity of olfactory navigation behavior in arthropods, its crucial role in animal survival and reproduction, and the conservation of underlying brain structures described above, we propose that addressing this question through a comparative study of the neural basis of olfactory navigation is likely to provide great insight into the organization and “functional logic” of neural circuit assembly.Drosophilia sechellia on the acidic noni fruit has been linked to increased sensitivity to noni odor in a specific ORN, OR22a, an increased number of OR22a neurons, and enlargement of the corresponding glomerulus (Auer et al. Drosophila species, evolution of odor preference during courtship behavior has been linked to changes in central, rather than peripheral, odor selectivity (Seeholzer et al. How do species-specific differences in olfactory navigation arise? The most notable differences between species include which odors are innately attractive or aversive, what temporal patterns of odor fluctuation are required to drive movement upwind or upstream, and the characteristic frequencies and timescales of behavioral features such as surging, searching, and stopping. Thus far, the most progress has been made in understanding cross-species differences in odor preferences, which are mostly driven by changes in the repertoire of olfactory receptors and the structure of peripheral olfactory circuits. For example, specialization by What tools and resources will be needed to more fully understand how the arthropod brain generates olfactory navigation behavior? A critical first step will be quantitative comparisons of search and navigation behavior across species in similar behavioral paradigms with well-controlled sensory stimuli. The explosion of tools for high throughput tracking and quantification of behavior using methods based on deep learning makes these previously challenging approaches newly possible (Mathis et al. Olfactory navigation is an ancient behavior that is critical for the survival and reproduction of most arthropod species. While the odors that drive attraction, the physical structure of odor plumes and trails, and the modes of locomotion differ greatly across arthropods, many of the core computations and behavioral motifs involved in getting to an odor source appear remarkably conserved. New tools for comparing the behavior, cell types, and organization of neural circuits across species have renewed interest in comparative approaches to understanding neural function. We propose that such comparative study of olfactory navigation in arthropods is likely to elucidate fundamental principles of neural circuit development, organization, and evolution.


Sleep is a fundamental aspect of human physiology that is crucial for maintaining physical and mental health. Despite its importance, many aspects of the relationship between sleep and brain function remain poorly understood. In this special issue on sleep function, we present a collection of articles that explore some of the most intriguing questions related to this complex relationship.Kokošová et al.).One of the most pressing questions in sleep research concerns the bidirectional association between sleep and brain atrophy in aging. As we age, our brains undergo a gradual process of degeneration that can lead to cognitive decline and dementia. Recent studies have suggested that poor sleep quality may accelerate this process by promoting brain atrophy, while conversely, sleep may help protect against brain degeneration .Another important aspect of sleep function is its relationship to visual attention. It is well-established that poor sleep quality can impair visual attention, but the precise mechanisms underlying this relationship are not fully understood. Recent studies have suggested that disruptions in the sleep-wake cycle may interfere with the activity of brain regions involved in visual attention, leading to deficits in this critical cognitive process .In addition to its impact on cognitive function, sleep also plays a crucial role in regulating the activity of nuclei involved in the sleep-wake cycle. Recent studies have identified two key hormones, leptin, and adiponectin, that appear to play a critical role in this process. These hormones help to regulate the activity of nuclei involved in sleep and wakefulness, leading to more restful and restorative sleep .Finally, recent studies have identified functional differences in cerebral activation between slow wave-coupled and uncoupled sleep spindles. These findings suggest that different types of sleep spindles may play distinct roles in memory consolidation and other cognitive processes. In this issue, we present several articles that explore the functional differences between slow wave-coupled and uncoupled sleep spindles, shedding new light on the intricate relationship between sleep and brain function (In conclusion, this special issue on sleep function highlights the latest advances in our understanding of the complex interplay between sleep and brain function. We hope that these articles will inspire further research in this fascinating field and ultimately lead to new treatments and interventions for sleep-related disorders.FG-G wrote and reviewed the manuscript.


Neonatal brain injury and associated inflammation is more common in males. There is a well-recognised difference in incidence and outcome of neonatal encephalopathy according to sex with a pronounced male disadvantage. Neurodevelopmental differences manifest from an early age in infancy with females having a lower incidence of developmental delay and learning difficulties in comparison with males and male sex has consistently been identified as a risk factor for cerebral palsy in epidemiological studies. Important neurobiological differences exist between the sexes with respect to neuronal injury which are especially pronounced in preterm neonates. There are many potential reasons for these sex differences including genetic, immunological and hormonal differences but there are limited studies of neonatal immune response. Animal models with induced neonatal hypoxia have shown various sex differences including an upregulated immune response and increased microglial activation in males. Male sex is recognized to be a risk factor for neonatal hypoxic ischemic encephalopathy (HIE) during the perinatal period and this review discusses in detail the sex differences in brain injury in preterm and term neonates and some of the potential new therapies with possible sex affects. Neonatal brain injury is associated with long-term neurodevelopmental disability and is more common in boys. There are many factors, pre-, peri- and post-natal, genetic and metabolic factors, which can interact and result in brain injury in the neonatal period . NeonataInflammation in the perinatal period results in the activation of the innate immune system and increased production of cytokines and some of the causes include chorioamnionitis, hypoxia-ischaemia and preterm birth . The actCytokines modulate inflammation and repair after inflammation-related brain damage. Altered cytokines have previously been described in infants with NE versus healthy control infants . The cytThis ongoing inflammatory “hit” augments the activation of resident immune cells in a process which prolongs the original inflammation and activates a secondary process of brain injury. The innate immune cells of the brain, microglia, become activated, monocytes, macrophages and neutrophils become activated and increase the release of proinflammatory cytokines. The blood-brain barrier becomes compromised and cross-talk occurs with the peripheral immune system leading to an ongoing inflammatory response .The tertiary phase of brain injury follows, spanning weeks to years after the initial insult and is characterized by persisting neuroinflammation, excitotoxity, and endogenous neuroregeneration and repair . PersistMale infants are at a higher risk of adverse outcome compared to females and have higher rates of morbidity and mortality compared to their female counterparts. This marked sexual dimorphism for outcome and mortality is especially pronounced in preterm infants . There iThere is a marked difference in immune response between males and females throughout life  with an Neonates largely depend on a developing immune system for mediating immune responses as their adaptive immune response and memory to pathogens develops rapidly over the first 3 months of life –42. NeonLeviton et al. demonstrated that repeatedly elevated concentrations of inflammation-related proteins such as tumour necrosis factor-a (TNF-α), tumour necrosis factor-a-receptor-1 (TNFR1), interleukin-8 (IL-8), intercellular adhesion molecule-1 (ICAM-1), interleukin-6 (IL-6), E-selectin, and insulin-like growth factor binding protein-1 (IGFBP-1), during the first 2 postnatal weeks  led to aNeonatal encephalopathy (NE) is the most common cause of neonatal brain injury occurring in term and near-term infants >35 weeks gestational age . NE encoInflammatory molecules secreted to allow communication between cells have been shown in multiple studies to be altered in infants with NE , 59. In Clinical studies in preterm and term infants are less frequently reported to animal studies on sex differences in brain injury, a recent review article details sex specific differences in brain injury and repair in infants . InflammDespite the higher incidence of such abnormalities in males, it has been suggested that extremely preterm male infants also have a higher risk of adverse neurological outcome in the absence of severe IVH or PVL . A recenNeonatal encephalopathy is a complex disease occurring in the perinatal period caused by a number of aetiologies such as hypoxia ischaemia, perinatal infection, neonatal stroke, infection and placental abnormalities , 75. In Sexual disparities are prominent with respect to immune function and preterm birth , 22. TheModulating innate immune responses may prove to be vital in the search for adjuvant treatments to improve outcome – medications under investigation at present include allopurinol, melatonin and erythropoietin . The ongClinical studies have shown that caffeine has neuroprotective effects in premature infants by alleviating hypoxia-induced white matter damage, and by improving ventilation function and brain self-regulation , 92. In The Trial of Indomethacin Prophylaxis in Preterm Infants (TIPP) used low-dose indomethacin on very low birth weight infants to determine if improvement in survival without cerebral palsy or developmental problems at 18 to 22 months of age could be achieved. The study results show that indomethacin reduced the incidence of patent ductus and of severe periventricular and intraventricular haemorrhage . Ment etvia IV and trans-epidermal routes can maintain plasma levels as high as those in utero with biological effectiveness  is the only available treatment in cases of neonatal encephalopathy. However, studies show it is effective in only 50% cases and adverse outcomes such as death, neurodevelopmental delay and severe disability occur in in the other half of cases . Recent Allopurinol is commonly used in the treatment of gout in adults. Animal studies have shown some promising data in relation to its potential in reducing the level of brain injury following perinatal asphyxia by reducing the number of oxygen radicals and combined with TH may benefit the neurodevelopmental outcome . In a CoZenon is a noble gas with an excellent safety profile in animal studies . Its useThere are various other therapies being designed to improve outcome for neonates with brain injury. In combination with TH, these therapies may play an important role in altering the inflammation seen in these infants as inflammation plays a critical role in the pathogenesis of neonatal brain injury. Erythropoietin (Epo) has anti-inflammatory, anti-oxidant and anti-apoptotic effects and promotes neurogenesis and angiogenesis. There are trials underway to determine its potential as a therapeutic agent in preventing adverse outcome in neonates with brain injury and inflammation. The Preterm Erythropoietin Neuroprotection Trial (PENUT) is a Phase III of high dose Epo for neuroprotection in the preterm infant that looked at a sex effect and found no difference in the treatment groups in relation to sex . A phaseThere are gaps in our knowledge within this topic. The first of these is that many clinical and laboratory studies have not reported results by sex, therefore limiting our insights into the potentially important differences in neonatal immunity between the sexes, future studies would benefit in reporting results with sex as a biological variable in all neonatal studies. Another important deficit in scientific investigation is the lack of study on postnatally acquired samples in neonates. At present much of our human data is from umbilical cord blood which, while easily obtainable, does not mirror the more clinically important postnatal immune system. There are a multitude of studies that show clear differences between males and females in their brain structure, response to hormones and response to treatments in terms of brain injury. The mechanisms responsible for these observed differences are still elusive. In terms of care of the newborn, particularly those with HI, it must be of importance in the treatment and interventions used, to take this sexual dimorphism into account to have optimal outcome for the infant , 129. ReLK and EM conceptualization. LK, AB, GS, EM writing original draft, LK and EM review and editing. All authors contributed to the article and approved the submitted version.