The burgeoning subfield of neuroscience focused on salubrious attributes of the human condition has begun to illuminate the complex biological basis of human functioning and flourishing. This has been referred to as positive neuroscience. Instead of focusing on pathology, research on positive neuroscience directs its attention on the neural mechanisms supporting flourishing, psychological well-being, resilience, and promotion of health. Previous studies have investigated the structural and functional neural basis underlying positive human functioning such as well-being  meta-analysis of functional magnetic resonance imaging (fMRI) studies to investigate whether neural systems involved in prosocial behaviors and reward demonstrated overlapping or distinct neural signatures. They found that prosocial behaviors specifically activated the insula, temporal lobe, and superior temporal gyrus (STG), whereas reward specifically activated the lentiform nucleus, thalamus, caudate nucleus, parahippocampal gyrus (PHG), and anterior cingulate cortex (ACC). Relatedly, Tunison et al. more specifically report on an event-related potential (ERP) component associated with reward processing, the reward-related positivity (RewP). The RewP is a positive deflection ERP component observed between 250 and 350 ms after reward feedback over fronto-central electrode sites, and its amplitude has been related to internalizing psychopathology. However, the RewP has been examined almost exclusively in response to financial rewards, and whether this ERP component is a general feature of reward processing remains uncertain. To address this, Tunison et al. used a point-based system of reward and found that RewP amplitudes were indeed larger for rewarded trials vs. non-rewarded trials. These data add to a growing literature that there are general properties of incentives regardless of the reward type.Hu et al. used functional near-infrared spectroscopy (fNIRS) to examine the brain's hemodynamic responses to different positive emotions. They found 10 typical kinds of positive emotions  could be divided into three distinct clusters  and hemodynamic responses to these three clusters showed distinct patterns. Second, using fMRI, Hong et al. explored the neural basis of a specific and rarely examined positive emotion type—professional pride. They found that professional pride may be associated with multiple brain networks including the right ventrolateral prefrontal cortex (VLPFC), left dorsolateral prefrontal cortex (DLPFC), left middle and inferior temporal gyri, left posterior superior temporal sulcus, right temporoparietal junction, left lingual gyrus, left calcarine cortex, right insula, left caudate, and right putamen. Third, Goldbeck et al. used resting state fNIRS to investigate neural basis of well-being. Performing a voxelwise regression, they found that the networks linked to individual differences in well-being included areas of the posterior default mode network. Interestingly, they found specific divergence in neural circuits linked to eudaimonic well-being, defined as a sense of meaning and purpose, positive social relationships, mastery, autonomy, virtues, and subjective well-being, a more general term referring to the various types of subjective evaluations of one's life, including both cognitive evaluations, and affective feelings  in regions linked to attentional control, interoception, and executive function, and decreased FC in regions linked to self-referential processing and mind wandering. In another study, Arkin et al. demonstrated that musical creativity was negatively associated with gray matter volume in the right inferior temporal gyrus and bilateral hippocampus. Motivated by Thayer et al.'s Neurovisceral Integration model  meditation could improve self-reported levels of mindfulness and reduce levels of anxiety and depression, while the subsequent 4-weeks open monitoring (OM) meditation could further improve the level of mindfulness and maintain a positive mood. Second, Kwak et al. explored the neural mechanisms underlying the effect of a 4-days meditation intervention on stress resilience using resting state fMRI FC. They found that increased resting-state FC between the left rostral ACC and the dorsomedial prefrontal cortex (dmPFC) was linked to neural basis of the effect of the meditation intervention on stress resilience that was assessed via the Resilience Quotient Test (RQT). Third, Tang et al. reviewed key components and potential brain-body mechanisms related to well-being and proposed mindfulness training as a promising method to improve well-being. Finally, Reddy and Roy further reviewed the role of one's motivation to engage in meditation practices. They proposed that while practicing meditation one may benefit from traditional assistance and ethical/moral teachings in addition to meditation training in isolation.Beyond positive personal characteristics, four studies explored the effect of mindfulness/meditation training on the brain and psychological functions. First, using a two-stage mindfulness training over eight weeks, DiMenichi et al. investigated the effect of expressive writing on neural processing during learning. A large literature finds that expressive writing is linked to healthy psychological function  exhibited a lower FC between the nucleus accumbens and frontal eye field (FEF) within the motivation network and a higher FC between intraparietal sulcus (IPS) and precentral gyrus (PCG) within the motivation network than non-KPs. Song et al. reviewed the underlying psychological and neural mechanisms that may underlie positive illusions and proposed that increasing positive illusions may be a promising way to improve relationships. Lastly, Zhu et al. used real-time fMRI neurofeedback (rtfMRI-NF) to investigate the capacity to self-regulate hippocampal activity. They found that hippocampal activity and amygdala–hippocampus connectivity can be regulated using rtfMRI-NF.Interestingly, several papers in this issue also report on the neural components linked to other positive activities  that can promote positive human functioning. For example, Takeuchi et al. investigated the effects of family socioeconomic status (SES) on brain structure. They partly replicated previously observed main effects of family SES on regional gray matter volume and fractional anisotropy. They also observed a significant interaction between sex and family SES in white matter tracts between areas such as the thalamus, corpus callosum, ACC and lateral PFC. The precise pathways by which these effects may manifest are open to debate.Finally, In summary, the articles presented in this Research Topic provide a valuable insight into understanding the biological bases of positive human functioning and flourishing, and highlight new and exciting directions for the field of positive neuroscience.All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The 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.


Environmental temperature is a key driver of variation in developmental physiological rates in reptiles. Cooler temperatures extend development time and can increase the amount of energy required to achieve hatching success, which can pose fitness consequences later in life. Yet, for locally-adapted populations, genetic variation can oppose environmental variation across ecological gradients, known as countergradient variation (CnGV). Biologists often seek to understand the presence of phenotypic variation, yet the absence of such variation across environmental gradients can also reveal insights into the mechanisms underlying local adaptation. While evidence for genetic variation opposing environmental variation in physiological rates has been summarized in other taxa, the generality of CnGV variation in reptiles is yet unknown. Here I present a summary of studies measuring development time and metabolic rates in locally-adapted populations across thermal clines for 15 species of reptiles across 8 families. CnGV in development time is found to be common, while no clear pattern emerges for the thermal sensitivity of metabolic rates across locally-adapted populations. CnGV in development time may be an adaptive response in order to decrease the costly development in cool climates, however, empirical work is needed to disentangle plastic from genetic responses, and to uncover potentially general mechanisms of local thermal adaptation in reptiles. Thermal regimes often vary considerably across spatio-temporal gradients, yet similar developmental phenotypes can be maintained when genetic variation opposes environmentally-induced variation . BiologiG,E)] can be either positive or negative, depending on whether they reinforce or oppose each other. There are three potential ways in which genotype-environment covariances can play out across populations. First, genotypes (G) and the environment (E) shift trait expression in the same direction, known as cogradient variation where the Cov term is positive  is negative], referred to as countergradient adaptation  or effects imparted later in life, for example reductions in size at hatching, growth rates and reproductive success . Low temD), or metabolic rate (MR) will increase the costs of development, and therefore reduce the amount of residual energy at hatching. The recently proposed Development Cost Theory (DCT) posits that the relative temperature sensitivities of D and MR determine the amount of energy expended at any given temperature  scales with temperature . Increasperature . At coolforaging , howeverforaging . Based oforaging . DCT canD or MR is statistically correlated with thermal gradient, three criteria must be met: (1) measures of the pattern of change in D and MR across a spatially or temporally varying environmental gradient; (2) the norm of reaction for D and MR in response to temperature; (3) a measure of the magnitude of thermal variation across the gradient. It is often difficult to unequivocally demonstrate that inter-populational divergence in thermal sensitivity of a trait is a result of adaptive genetic divergence, and not due to a plastic response. Obtaining evidence for CoGV and CnGV requires collecting data from common garden or reciprocal transplant studies, conducted across a range of temperatures in order to distinguish between VGxE and Cov  are acting simultaneously when norms of reaction are not parallel and do not cross  . Norms oD) and metabolic rate (MR) across cold- and warm-adapted populations of reptiles (D and MR across climatic regimes (D and (or) MR across a species’ thermal gradient, relative to warm-adapted populations. Reptiles provide a useful model system to study local adaptation because developmental trajectories in reptiles are highly sensitive to environmental temperatures  = 0; G,E) > 1; G,E) < 1; D and (or) MR under thermal change then evolution is likely the result of CnGV, whereas rapid trait divergence in D or MR in the direction of thermal change is due to the evolution of CoGV. Due to the paucity of data on thermal sensitivity of D and MR, it is not yet feasible to present a formal, comprehensive meta-analysis on the topic here. Rather, this review serves as a summary of existing data on thermal reaction norms across locally adapted populations, and points toward future avenues of research that require further work in order to continue developing our understanding of adaptation along thermal gradients.It is important to develop a clear understanding of patterns of countergradient variation in nature, before designing experiments to evaluate causal mechanisms . This pareptiles . Effect  regimes . It is aeratures , and maneratures . This reg (D); D) across climatic regimes. Development under cool conditions necessitates a countergradient adaptive response for faster development and earlier hatching time, enabling embryos to hatch before winter while resources are still available (MR) – overall, reptile embryos from locally-adapted cooler climates did not maintain higher metabolic rates compared with populations from warmer climates  vs. urban (hot) populations of ulations . These fulations . DecreasD – reducing development time may come at the cost of embryos hatching at smaller sizes and reduced juvenile growth rate , which is a limitation of studying species with relatively long generation times, such as reptiles and other vertebrates (Finally, it may be that interactions between genotype and environment are inflating observations of CnGV across thermal regimes, and that CnGV in development time is less common than currently assumed. There may be genotype-dependent effects of environment on development time, where for example, a single genotype is superior in all environments, even though the slopes of reaction norms differ (see Box 2 in tebrates .Adaptation of developmental physiological rates is an important, yet underutilized avenue of research for understanding population persistence under changing and novel environments. Countergradient variation for traits expressed later in the life history have been well documented in reptiles, including growth , body siDevelopmental and metabolic rates under selection may in turn affect selection on genetically correlated traits later in life . ResolviAcross latitudinal and altitudinal clines, cold-adapted populations have genetic capacity for faster development, relative to warm-adapted populations. While these differences in thermal sensitivity to local temperatures did not extend to warm- vs. hot-adapted populations such as forested vs. city populations, there is overall support for common CnGV in development time in reptiles, which mirrors findings observed in other taxa . Given tAP conceived of the idea, collected the data, and wrote the manuscript.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Cutaneous metastases can be either the initial presentation of an unsuspected internal neoplasm in a cancer-free individual, or the harbinger of recurrent malignancy in an oncology patient who had achieved remission of his cancer, or a sign of progressive disease in a cancer patient who is currently receiving antineoplastic treatment. The cutaneous presentation of skin metastases is pleomorphic and can mimic not only benign conditions and tumors of the skin but also infections and inflammation of the skin. Carcinoma erysipelatoides, carcinoma hemorrhagiectoides, and carcinoma telangiectoides are the three subtypes of inflammatory cutaneous metastatic cancer. The former masquerades as a cutaneous streptococcal infection whereas the latter mimics idiopathic telangiectasias. In contrast, the morphology of carcinoma hemorrhagiectoides is distinctive: it appears similar in shape to a medieval knight’s shield and its presence is referred to as a positive shield sign. To the best of our knowledge, carcinoma hemorrhagiectoides has been reported in four oncology patients whose skin metastases presented with the shield sign: two men with salivary duct carcinoma and two women with breast cancer. In conclusion, the shield sign may not only be a pathognomonic clinical feature of carcinoma hemorrhagiectoides but also reflect a common genomic aberration of these metastatic tumors. Cutaneous metastases do not occur frequently. Typically, when they do appear, it is in the setting of an oncology patient whose visceral malignancy is progressing. However, albeit less often, they may be either the initial presentation of malignancy in a previously cancer-free individual or the heralding sign of cancer recurrence in a patient whose malignancy had been in remission -19.The morphology of cutaneous metastases is variable. In addition to cutaneous conditions and benign neoplasms, skin metastases can mimic infection diseases -7. CutanCarcinoma hemorrhagiectoides is a subtype of inflammatory cutaneous metastases -11; it hPleomorphic presentation of cutaneous metastasesThe morphologic presentation of cutaneous cancer metastases can mimic benign skin tumors, dermatologic conditions, and vascular lesions. The nodular lesions of metastatic carcinoma can mimic dermatofibromas. Metastatic carcinoma can also appear similar to dermatitis (in patients with inframammary crease skin metastases and Paget disease), hair loss , periobital edema (in patients with painless eyelid swelling), and scleroderma (in patients with carcinoma en cuirasse) ,4.Specific tumor-associated cutaneous metastases morphologiesCutaneous metastases from specific cancers can be variable in their presentations. Breast cancer metastases to the skin commonly present as nodules. However, they can appear as bullae, inflammatory carcinoma metastases , or plaques -5,8,12.Cutaneous breast metastases can also mimic other conditions  or tumors (such as keratoacanthoma and melanoma). They are most frequently found on the skin of the ipsilateral affected breast. However, they can be located on the opposite breast skin, inframammary fold, periocular area, scalp, subungual region, and umbilicus -5,8,12.In contrast to breast cancer cutaneous metastases, other malignant neoplasms, such as metastatic neuroblastoma, have fewer clinical presentations of cancer-associated skin metastases that have been observed. Neuroblastoma cutaneous metastases typically present as blue-gray nodules that blanch after stroking. However, they also can appear as periorbital ecchymoses and heterochromic iridis .Salivary duct carcinoma is a rare malignancy derived from the parotid glands; to our best knowledge, only six salivary duct carcinoma patients with cutaneous metastases have been described: five men and one woman ,14-19. TTwo of the other men’s salivary duct carcinoma skin metastases presented as subcutaneous nodules that were either skin-colored on the scapula and suprapatellar areas or zosteriform and linearly distributed on the chest and neck -18. The Cutaneous metastases masquerading as infection or other conditionsSkin metastases can masquerade as bacterial infections such as cellulitis (in patients with carcinoma erysipelatoides) or acute paronychia. They can also occur in a zosteriform distribution similar to varicella zoster virus infection. In addition, the metastatic cancer can appear as granulation tissue (pyogenic granuloma-like), or palpable purpura (mimicking vasculitis), or similar lymphangioma circumscriptum (in patients with carcinoma telangiectoides) -7.Inflammatory cutaneous metastasesThere are three variants of inflammatory cutaneous metastatic cancer: carcinoma erysipelatoides, carcinoma hemorrhagiectoides, and carcinoma telangiectoides Table  8,9].,9.8,9].Carcinoma erysipelatoidesCarcinoma erysipelatoides presents as a sharply demarcated erythematous patch or plaque. It mimics a streptococcal infection of the skin. The tumor cells infiltrate the lymphatic vessels and are minimally present (or absent) in the dermis ,9.Carcinoma telangiectoidesCarcinoma telangiectoides presents as an erythematous patch with prominent telangiectasias. It can mimic idiopathic telangiectasias. However, the tumor cells usually infiltrate the blood vessels and are minimally present (or absent) in the dermis ,9.Carcinoma hemorrhagiectoidesCarcinoma hemorrhagiectoides was initially described in 2012 in two men with metastatic salivary duct carcinoma , cancer recurrence (one man), or initial presentation of malignancy (one woman). The erythematous, purpuric, and violaceous color of the metastatic infiltrated plaque or macule produced a hemorrhagic appearance; angiokeratoma-like lesions, bullae, papules, and pseudovesicles were also present. In addition to the chest, all patients had concurrent skin metastases at other sites -11.Microscopic examination demonstrated tumor cells throughout the dermis. In addition, tumor cells were also within lymphatic vessels. Some of the patients also had tumor cells in blood vessels or the subcutaneous fat -11.In general, the appearance of cutaneous metastases is not a favorable development for a cancer patient. However, both of the men with salivary duct carcinoma demonstrated a dramatic improvement of their neoplastic disease after receiving treatment with temsirolimus and bevacizumab; yet, both men died shortly after initiating treatment: the 70-year-old man from a myocardial infarction and the 73-year-old man from progressive disease after stopping therapy ,15. The Carcinoma hemorrhagiectoides is a distinctive morphologic presentation of cutaneous metastatic carcinoma. The clinical presentation of papules with an underlying indurated violaceous plaque correlates with the pathology findings of tumor infiltration not only in vessels-blood, lymphatic, or both-but also extensively throughout the dermis. To date, carcinoma hemorrhagiectoides has only been observed in breast cancer patients with metastatic adenocarcinoma or invasive ductal carcinoma, as well as in oncology patients with metastatic salivary duct carcinoma. Similar to the men with salivary duct carcinoma, the distribution of the cutaneous metastases in the women with breast cancer also resembled a medieval knight’s shield that was extending across their chests. We suggest that the shield sign may be a pathognomonic clinical feature of carcinoma hemorrhagiectoides and speculate that it may reflect a common genomic aberration of these tumors.


However, cancer-specific metabolic adaptations also introduce vulnerabilities that can be exploited clinically. Since the implementation over a half-century ago of chemotherapeutic anti-metabolite drugs such as methotrexate, a folate cycle inhibitor, new pharmacological approaches focussed on targeting metabolic pathways are in trial, and, recently, novel defined dietary regimens aimed to aid cancer therapy have come to the fore.3 In particular, modulation of serine and glycine availability is proven to be effective in inhibiting the growth of specific subtypes of tumour in vivo.4 These non-essential amino acids, which can be synthesised from glucose, are pivotal substrates for several metabolic pathways, including the biosynthesis of proteins and nucleic acids. However, the molecular mechanism behind the ability of serine-free diet to restrict tumour growth, with respect to alteration in the cancer lipodome remains uncharted. In a recent publication in Nature, Muthusami et al.1 explore the effect of tumour serine restriction on sphingolipid heterogeneity, highlighting the promiscuity of SPT as a metabolic liability of cancer cells that can be exploited through diet or pharmacological means.Tumour cells acquire a range of metabolic adaptations, driven directly and indirectly by genetic mutations, making altered cellular metabolism a hallmark of cancer.1 performed [U-13C6]glucose and alanine tracing in both adherent and spheroid cultures. Interestingly, upon MPC inhibition or knockdown, the authors observed that spheroid growth was boosted, secretion/accumulation of alanine was rescued and serine synthesis increased. Specifically, the authors demonstrated in spheroid cultures that while glucose metabolism was diverted towards the serine synthesis pathway, alanine flux into the TCA cycle was increased, bypassing the inactivity of MPC. Hence, Muthusami et al.1 hypothesised that alanine could be deleterious for anchorage-independent growth; the authors showed that the advantage given by the lack of the MPC was abrogated by exogenous alanine supplementation. Likewise, a comparable effect was achieved by serine/glycine depletion, suggesting a connection between the two events.The authors began by comparing the metabolic changes induced in cancer cell lines by attachment-independent (spheroid) growth, finding increased secretion and intracellular accumulation of alanine along with a decreased flux through the pyruvate dehydrogenase enzyme. Since previous reports have shown that inhibition of the mitochondrial pyruvate carrier (MPC) is able to decrease alanine levels in adherent cultured cells, to further investigate the correlation between the alanine accumulation and altered mitochondrial metabolism, Muthusami et al.1 compared the kinetics of different serine-consuming enzymes and SPT displayed a Km within intratumoral serine concentrations, thus limiting its affinity for serine in serine-restricted conditions. Under normal conditions SPT catalyses sphingosine synthesis using serine as a substrate. However, SPT displays substrate promiscuity, and during serine restriction can switch to alanine , a precursor of complex membrane lipids, suggesting an altered membrane composition. Furthermore, the authors showed increased expression of the liver enzymes involved in alanine degradation, suggesting putative alanine scavenging activity of the liver and prevention of the accumulation of toxic lipid species.Next, the authors investigated this newly identified vulnerability in the context of in vivo physiology using xenograft models coupled with pharmacological and dietary intervention. In similarity to recent studies, the authors demonstrated that upon serine and glycine starvation tumour progression was significantly decreased.1 rescued in vivo tumour growth by inhibiting SPT concurrent with a serine and glycine-restricted diet. While at high dose the SPT inhibitor displayed a systemic harmful effect, at lower drug concentration the authors observed stable liver function and restored xenograft growth despite limited serine availability. Finally, the authors employed an alternative means to decrease serine availability, by administering a phosphoglycerate dehydrogenase  inhibitor that significantly reduced both plasma and tumour levels of serine and glycine concomitantly with toxic deoxysphingolipid accumulation.To validate the proposed mechanism, Muthusami et al.5 such as protein synthesis, folate-dependent one-carbon metabolism (for nucleotide synthesis) and glutathione synthesis, it seems likely that toxic metabolite accumulation is one of several metabolic outcomes of serine and glycine limitation that could contribute concurrently to impeding tumour growth. It is technically challenging to dissect the exact contribution of each process as inhibiting/supplementing one metabolic pathway will likely modulate the serine availability for use by alternate pathways, making it difficult to isolate the importance of any individual pathway. Interestingly, the promiscuity of SPT is not limited to serine and alanine, but also to palmitoyl-CoA and other acyl-CoA species, suggesting a more intricate and complex network of stress signals via tuning cellular lipid diversity that could prompt further research for new therapies.This study has elegantly highlighted the possibility of exploiting promiscuous enzymes such as SPT to treat cancer by limiting the availability of the primary substrate, leading to the production of toxic lipid species, altering cellular membrane composition and ultimately impairing tumour growth. Importantly, it was demonstrated that tumour cells were more susceptible to this intervention than healthy tissues, giving a clear therapeutic window for this approach. Given the importance of several other serine/glycine-dependent pathways in cancer cell metabolism,


Aging is an inevitable and gradually progressive process affecting all organs and systems. The musculoskeletal system makes no exception, elderly exhibit an increased risk of sarcopenia (low muscle mass),dynapenia (declining muscle strength), and subsequent disability. Whereas in recent years the subject of skeletal muscle metabolic decline in the elderly has been gathering interest amongst researchers, as well as medical professionals, there are many challenges yet to be solved in order to counteract the effects of aging on muscle function efficiently. Noteworthy, it has been shown that aging individuals exhibit a decline in skeletal muscle metabolism, a phenomenon which may be linked to a number of predisposing (risk) factors such as telomere attrition, epigenetic changes, mitochondrial dysfunction, sedentary behavior , age-related low-grade systemic inflammation (inflammaging), hormonal imbalance, as well as a hypoproteic diet . The present review aims to discuss the relationship between old age and muscle wasting in an effort to highlight the modifications in skeletal muscle metabolism associated with aging and physical activity. Aging is an inevitable process affecting all organs and systems . The musSkeletal muscle assures locomotion as well as certain important aspects of metabolic homeostasis, such as glucose uptake and fatty acid oxidation . Among oFrom debilitating comorbidities , inactivThe present review aims to discuss the relationship between old age and muscle wasting in an effort to highlight the changes in skeletal muscle metabolism associated with aging and physical activity.In recent years, the subject of cell senescence (derived from the Latin word senescere portraying age-related decline or waning) has been studied intensely . In the Skeletal muscle cells demonstrate longer telomeres compared to leukocytes. However, telomere shortening has been shown to progress at similar rates in minimally proliferative tissues  and proliferative cells (such as skin cells and leukocytes) . NeverthIt has been reported that the amassing of connective tissue in muscles together with lipid molecule build-up   inside mSarcopenia and dynapenia are highly prevalent in the elderly as well as in chronic conditions  30,31,3,331,32. While not yet fully understood, the pathomechanisms underlying sarcopenia and dynapenia, have become a legitimate subject of research in recent years . Fabbri In the elderly, the dynamics of energy production and usage are disrupted ,37. ThisRanging from DNA methylation/demethylation to histone acetylation/deacetylation processes, a wide variety of epigenetic alterations have been thought to modulate skeletal muscle metabolic activity  40]. In. In40]. Certain chronic conditions such as type II diabetes mellitus and neuromuscular diseases, as well as age-related loss of muscle mass, have been shown to associate with epigenetic changes, consequently, leading to modifications of skeletal muscle metabolic activity . HoweverEndurance exercise has been shown to decrease global DNA methylation in young sedentary individuals. In mice  as well Motor units within skeletal muscles may be stratified according to the type of myosin dimers displayed by the fibers. Specifically, type I myosin demonstrates an abundance of mitochondria and myoglobin, in this case, ATP deriving from oxidative metabolic processes. Type I myosin characterizes low fatigable motor units in which it is capable of transducing energy over lengthier periods of time at a relatively decreased pace . ContrasIn elderly sarcopenic individuals, type II muscle fibers have been shown to be more prone to atrophy compared to type I predominantly in postural muscles. However, studies report discrepant results with regard to the proportion in which the cross-sectional area of fast fatigable (type II) or slow fatigable fibers (type I) decreases with aging . In thisAge-related dysregulations in motor units may translate into significant disability. Nevertheless, an aging-related conversion of slow fatigable fibers into fast fibers, as well as an increment of hybrid fibers, have been observed . It has Murgia et al. analyzed the impact of aging on skeletal muscle from a single-fiber proteomic perspective (mass spectrometry-based proteomics) in eight physically active older versus younger adults (widely spaced with respect to age) in an effort to eliminate the important confounding factors that are inactivity and immobilization in the elderly . NumerouVigelsø et al. compared biopsies from the vastus lateralis of endurance-trained middle-aged men to that of controls (untrained), finding higher contents of perilipin 5, endothelial lipase , and mitochondrial complex III–V in trained individuals .The accumulation of certain bioactive lipids such as ceramide and diacylglycerols(DAGs) at the level of skeletal muscles has been linkedto insulin sensitivity in experimental animals and human subjects ,54. It hThe mitochondrion is a highly dynamic organelle that holds a pivotal role in energy production as well as the release of ROS . MoreoveAdvanced age is associated with remarkable bioenergetic and biochemical changes in skeletal muscle mitochondria  56]. In. In56]. Sirtuin-3  is an NAD+–dependent protein deacetylase exerting regulatory properties on mitochondrial activity. In murine models of diabetes, its expression in skeletal muscle is reduced leading to anomalies in ROS production and insulin signaling . MoreoveMenshikova et al. investigated the discrepancies in mitochondrial size and content in the skeletal muscles  of overweight/obese older individuals undergoing either physical training or calorie restriction . In the Seeing as there is a growing body of evidence supporting the association between advanced age and body composition alterations, medical professionals are becoming increasingly aware of the challenges posed by aging in the general population .The European Working Group on Sarcopenia in Older People (EWGSOP) published a consensus report advancing diagnosis criteria for sarcopenia. The aforementioned criteria propose the evaluation of the decline in skeletal muscle mass together with strength and physical performance, thus arguing against the separation of sarcopenia from dynapenia .However, other authors defend the concept of a disproportionate decline between muscle mass and strength in old age, with dynapenia possibly progressing more rapidly than the decrease in muscle size . In addiPart of the data resulting from the Health, Aging, and Body Composition Study   includedIn older individuals, the balance between protein synthesis and breakdown may be hindered. Increased muscle catabolism and the reduction of skeletal muscle mass both characterize old age and frailty. It has been reported that frailty enhances the development of aging-related disruptions of protein metabolism . The lacDietary protein intake has often been shown to be below the recommended daily allowance in both men and women. In addition, research focusing on dietary intake for efficient stimulation of protein synthesis concluded that the optimal daily consumption falls within 1.2 and 1.5 g/kg ,73. CurrWhereas middle age is characterized by weight gain in both men and women, elderly individuals experience a decrease in body mass, which differs according to gender. In this regard, it has been found that weight loss in old age occurs earlier in men compared to women . In contAs of recent discoveries, white adipose tissue is no longer considered only a mean of storing excess energy, its active and dynamic secretory activity being described by numerous studies ,77. In tObesity is frequent among older sedentary individuals and has been shown to associate with both adipocyte hyperplasia and hypertrophy, thus triggering an imbalance between pro- and anti-inflammatory adipokine release  76,78,8,84.In centenarians, enhanced leptin levels have been linked to increased longevity. Moreover, sarcopenic individuals exhibit lower leptin titers . Seeing Several pathological conditions are associated with sedentary behavior, sarcopenia, and increased fat mass. Leptin levels have been shown to be increased in patients with spinal cord injuries . Yet sarThe amount of intermuscular fat located in the lower extremities may impact skeletal muscle quality and performance in certain populations such as older subjects. Moreover, it has been reported that intermuscular adipocytes secrete inflammatory mediators, thus creating an inflammatory microenvironment that is partly responsible for the appearance of alterations in the local blood supply . In thisBy promoting the accumulation of inflammatory cells within skeletal muscles and the simultaneous boosting of pro-inflammatory responses at the level of intermuscular fat, obesity ultimately leads to muscle inflammation. These phenomena incite the appearance of notable anomalies in myocyte metabolism . MoreoveApart from its role in assuring the erect posture in humans as well as locomotion, skeletal muscle tissue has long been proven to regulate global glucose metabolism ,91. ReseRelative to rest periods, the fractional production rate of myofibrillar proteins may be raised by exercise in sedentary older men, with better results at 24- and 48-h post-exercise in patients undergoing resistance training compared to HIIT . NeverthIn recent studies, skeletal muscle emerges as an important secretory organ with a plethora of roles in the control of global homeostasis. Myokines are thought to be mainly secreted by muscles but may also be released by hepatic, pancreatic, and adipose tissues . These pApelin is an adipomyokine whose release may be upregulated by endurance training in individuals with excess weight . It has Huh et al. found higher irisin values in younger versus older research subjects, studies reporting an inverse relationship between age and circulating irisin titers . Irisin In vitro research indicated that primary human skeletal muscle cells (HMSCs) treated with irisin suffer alterations in the expression of metabolic genes. In this respect, the upregulation of such genes involved in glucose metabolism as hexokinase 2 (HK2) and glucose transporter 4 (GLUT4) was observed as early as si hours post-treatment by Huh et al. . The uprChang et al. found a link between muscle dysfunction and irisin titers in the elderly, considering it to be a potential biomarker for sarcopenia. However, the authors used ELISA kits to determine circulating levels of the myokine . NeverthIt has been stated that the adipokine resistin blunts human myogenesis through the activation of the NFκB pathway (a negative regulator of myogenesis), especially in obese older individuals . O’LearyThe aging process is accompanied by variations in hormonal release , testosterone levels displayed an acute decrease (with a subgroup fulfilling androgen deficiency criteria). In contrast, preliminary findings revealed that the subjects’ physical performance was enhanced .Murine studies showed that estrogen could upregulate glucose uptake by promoting the phosphorylation of certain proteins involved in the insulin signaling pathway, which, in turn, may bolster the translocation of glucose transporter 4 (GLUT4) to the muscle cell membrane ,126,127.Marked disruption of the hypothalamic-pituitary-adrenal axis has been described in aging and certain chronic diseases ,132, incGhrelin is an important modulator of appetite and metabolism, and aging has been associated with decreased circulating levels of the hormone . DisplaySome authors found that ghrelin deletion in young experimental animal models did not lead to significant modifications in body composition. Following ghrelin deletion, mouse models of age-related skeletal muscle changes demonstrated a rise in the number of oxidative and fatigue-resistant type IIa muscle fibers . In addiOld age is known to be associated with a decrement in insulin sensitivity; the hormone exhibiting important anabolic effects on skeletal muscles . AdiponeBucci et al. investigated the impact of a four-month physical training program on skeletal muscle insulin sensitivity in a group of elderly women . The eldWhereas aging-associated hormone imbalance and its impact on skeletal muscles continue to attract interest from researchers, extensive analysis is needed to fully decode the intricate mechanisms underlying these processes, as well as to elucidate the potential impact of physical exercise . According to recent studies, aging is associated with a low-grade yet persistent accrual of such inflammatory biomarkers as IL-6, tumor necrosis factor α (TNF-α), and C-reactive protein (CRP), depicting a phenomenon widely known as inflammaging ,151,152.Systemic inflammation plays a significant role in the body composition decline of the elderly ,156. The“Adaptive aging” refers to the achievement of a balance between pro- and anti-inflammatory mediators in older persons . It has The aging process is associated with notable changes in muscle mass, structure, and function. Importantly, aging individuals exhibit a decline in skeletal muscle metabolism, a phenomenon which may be linked to a plethora of predisposing (risk) factors such as telomere attrition, mitochondrial dysfunction, physical inactivity, hormonal changes, age-related low-grade systemic inflammation (inflammaging), as well as a hypoproteic diet . Whereas in recent years, the subject of skeletal muscle metabolic decline in the elderly has been gathering interest amongst researchers as well as medical professionals, there are many challenges yet to be solved in order to efficiently counteract the effects of aging on muscle function.


Dear Editor,In this historical moment (COVID-19 infection spreading worldwide), we think it is interesting to know whether balneotherapy applications as mud-bath therapy or hydrotherapy applications can affect the immune system. Many mineral-rich waters have been shown to have effects on the immune system and recent findings suggest that balneotherapy may improve the efficacy of immune response. The mechanisms through which immersion in mineral-rich water or mud therapy may be useful to improve human immune function are still not completely understood, but surely neuroendocrine and immunological responses, including both innate and adaptive immunity, and also cell-mediated and humoral immunity, are involved.Concerning cell-mediated immunity, balneotherapy applications can improve the survival capacity and activity of neutrophils. Rinaldi et al.  demonstrMycobacterium tuberculosis); Th2 cells regulate humoral immunity and allergic responses, whereas the Th17 family is involved in the defence against extracellular pathogens. Th17 cells are pro-inflammatory lymphocytes, while Treg cells have a suppressor activity. A fine balance between Th17 and Treg CD4+ lymphocytes has emerged as a crucial point in the inflammation associated with autoimmune and immune-mediated diseases. Sulphur balneotherapy seems to have a role in the activation of both polarization pathways  may improve human immune function, both humoral and cell mediated. Due also to the variety and heterogeneity of balneotherapy modalities, characteristic of applications, water and mud compositions, the possible presence of radioactive properties, it might be interesting to explore this topic. However, we believe that the spas, if hygienically controlled, respecting WHO and national recommendations, can be visited for balneotherapy applications even in these days in which the world is struggling against COVID-19.


Atherosclerosis, a chronic inflammatory disease of the arterial wall, is among the leading causes of morbidity and mortality worldwide. The persistence of low-grade vascular inflammation has been considered to fuel the development of atherosclerosis. However, fundamental mechanistic understanding of the establishment of non-resolving low-grade inflammation is lacking, and a large number of atherosclerosis-related cardiovascular complications cannot be prevented by current therapeutic regimens. Trained immunity is an emerging new concept describing a prolonged hyperactivation of the innate immune system after exposure to certain stimuli, leading to an augmented immune response to a secondary stimulus. While it exerts beneficial effects for host defense against invading pathogens, uncontrolled persistent innate immune activation causes chronic inflammatory diseases. In light of the above, the long-term over-activation of the innate immune system conferred by trained immunity has been recently hypothesized to serve as a link between non-resolving vascular inflammation and atherosclerosis. Here, we provide an overview of current knowledge on trained immunity triggered by various exogenous and endogenous inducers, with particular emphasis on its pro-atherogenic effects and the underlying intracellular mechanisms that act at both the cellular level and systems level. We also discuss how trained immunity could be mechanistically linked to atherosclerosis from both preclinical and clinical perspectives. This review details the mechanisms underlying the induction of trained immunity by different stimuli, and highlights that the intracellular training programs can be different, though partly overlapping, depending on the stimulus and the biological system. Thus, clinical investigation of risk factor specific innate immune memory is necessary for future use of trained immunity-based therapy in atherosclerosis. Atherosclerosis, the major contributor for cardiovascular diseases, has been one of the leading causes of morbidity and mortality globally , 2. In eThe innate immune system, which includes monocytes and macrophages, plays a fundamental role in the preservation of immune homeostasis by eliminating infectious agents and promoting tissue damage repair. However, under pathological conditions as mentioned above, it is also responsible for chronic inflammatory diseases such as atherosclerosis. In recent years, a growing body of evidence has demonstrated that the innate immune system can build immunological memory of the past foreign encounters –11, chalAtherosclerosis is characterized by non-resolving arterial inflammation in which monocytes/macrophages play a central role, and any factors that promote this inflammation can significantly enhance the development of atherosclerosis. Meanwhile, the persistent activated phenotype of innate immune cells resulting in an exacerbated pro-inflammatory response is a hallmark of trained immunity. Using experimental models of trained immunity, it has been shown that cells related to atherosclerosis can be trained to develop a long-term pro-inflammatory and pro-atherogenic phenotype. In this regard, it is reasoned that trained immunity can act as an important driver of inflammatory atherosclerosis.−/− mice), short-term treatment of lipopolysaccharide (LPS) in a super-low-dose that mimics chronic infection elicits the polarization of monocytes into a sustained pro-inflammatory state with upregulated Ly6C, CCR5, MCP-1, and decreased SR-B1 expression level, and the result of which is the aggravation of atherosclerosis  vaccination, microorganisms, and microbial products, the monocytes/macrophages have been shown to build a long-lasting memory of this encounter leading to an enhanced pro-inflammatory response upon a subsequent challenge, and the resultant protective effect against reinfection is independent of adaptive immune system –22. Whilclerosis . In addiclerosis , 28–30. clerosis , 28–30. clerosis . Of noteclerosis . The finin vivo promotes expansion of hematopoietic stem and progenitor cells (HSPCs) and enhances myeloid differentiation through sustained transcriptional and metabolic modulation (−/− mice) showed that the sterile inflammatory Western diet (WD), which has been known as a risk factor of ASCVD, can similarly trigger hematopoietic precursor cell expansion and myelopoiesis associated with long-term transcriptional and epigenetic reprogramming of myeloid progenitor cells , bone marrow progenitor cells (hematopoietic and myeloid progenitor cells), and vascular non-immune cells  have been identified to be integral to trained immunity that potentially drives vascular inflammation. Trained immunity carried by these various cell types are likely to act cooperatively With the establishment of the emerging concept of trained immunity, considerable studies have focused on its potential mechanisms. It is currently believed that trained immunity is driven by a series of comprehensive signaling, metabolic, and epigenetic processes. For an individual myeloid cell, immunological challenges are first sensed by certain receptors, triggering specific trained-immunity-inducing signaling pathways that subsequently mediate long-term metabolic and epigenetic adaptations, eventually leading to a heightened innate immune response upon re-stimulation. On a systems level, stimulated bone marrow progenitors undergo transcriptional, metabolic, and epigenetic remodeling, which facilitates their more robust secondary response, as well as that of their progeny cells, to subsequent challenges. In addition, recent findings also suggested that the induction of cellular memory in non-immune cells may share similar mechanisms with innate immune training . While ain vitro and in vivo, indicating the essential role of mTOR signaling-mediated glycolysis in inducing trained immunity  compared to hypertensive controls, the circulating monocytes of PA patients do not show cellular reprogramming associated with in vivo induction of trained immunity   . Therefoabolism) .in vitro or experimental animal models. Indeed, epigenetic remodeling in trained immunity has been shown to induce the priming of genes that are involved in different stages of atherosclerosis from the initial foam cell formation to the eventual atherosclerotic plaque rupture, as well as genes directly associated with inflammation  approach, an increased glucose metabolism can be revealed in human atherosclerotic plaques especially regions of inflammatory cell infiltration and lipid-rich necrotic core –80. Moreex vivo differentiation into macrophages, leading to a heightened pro-inflammatory response that could drive systemic and vascular inflammation (The more compelling evidence of the involvement of trained immunity in atherosclerosis comes from the circulating monocytes. It was shown that monocytes in patients with atherosclerotic coronary artery disease are primed for an pro-inflammatory state which can still persist upon their ammation . Mechaniammation . Similarammation . Remarkaammation . In addiammation , 83 and ammation .Chronic inflammatory disorder including rheumatoid arthritis, obesity, diabetes, and metabolic syndrome has been considered as a major risk factor of ASCVD, independent of traditional ASCVD risk factors. Driven by systemic inflammation, a remarkable feature of these chronic inflammatory conditions is an enhanced myelopoiesis and a sustained over-activation of the innate immune system, which could in turn contribute to atherosclerosis , 85. Thiin vitro or experimental animal models, clinical translation of these knowledge aimed at targeting trained immunity to treat ASCVD should be cautious. For example, monocytes from patients with symptomatic atherosclerosis, which show a trained immune phenotype, undergo epigenetic rewiring with a reduced histone mark H3K4me3 on pro-inflammatory genes, contrasting an increase of H3K4me3 in the in vitro model of trained immunity (in vitro, it fails to revert the pro-inflammatory state of monocytes from patients with hypercholesterolemia that develop a trained immunity phenotype (in vivo situation in terms of metabolic and epigenetic reprogramming, thus more work is needed to further reveal the molecular mechanisms of trained immunity in human physiological and pathological settings. It is also important to note that the trained cellular states at the molecular and physiological levels are not uniform depending on the initial training stimulus (Of note, although trained immunity has been hypothesized to drive atherosclerosis , 13–17, immunity . Besideshenotype . These fstimulus . Since pin vivo system, limiting their clinical translation for treating atherosclerosis. Consequently, deeper understanding of the molecular mechanisms of trained immunity and its relevance for atherosclerosis development especially under human pathological conditions will allow the future development of new strategies targeting trained immunity for cardiovascular disease prevention and management.Non-resolving low-grade inflammation mediated by the innate immune system plays a central role in the pathogenesis of atherosclerosis and its related cardiovascular events. Although our understanding of the pathophysiology of atherosclerosis has leapt forward in recent years, the fundamental mechanisms underlying the establishment of non-resolving inflammation characteristic of atherosclerosis remain elusive. Trained immunity, an emerging new concept refers to a prolonged hyperactivation of the innate immune system triggered by various exogenous and endogenous stimuli, has been proposed as a potential contributor for the non-resolving inflammation conducive to atherosclerosis. Here, we review current understanding of the mechanisms that control trained immunity both at the cellular level and a systems level , 2, withCZ and JY designed and drafted the work. XY, YF, and JY reviewed and critically edited the manuscript. All authors read and approved the final manuscript.The 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.


A developmental perspective in psychiatry may be helpful in the refinement of phenotypes, etiologies and trajectories2: this perspective is essential, particularly in those clinical conditions with established neurodevelopmental antecedents, i.e., phenotypic features already manifest in premorbid phases. Indeed, as somehow implicit in the use of the apparently neutral term of “antecedents”, it is still unclear whether these impairments generate ex novo risk for subsequent psychopathology or merely represent a temporally pristine manifestation  of underlying neurobiological liability. Schizophrenia, for example, is often antedated by an interrelated constellation of childhood impairments7, as recently corroborated also by polygenic risk score (PRS) studies, confirming specific associations of schizophrenia PRS with a cascade of mutually reinforcing endophenotypic manifestations at the cognitive, social, emotional and behavioral levels since infancy through childhood to adolescence11.Adopting a developmental perspective could be a crucial maturational step to improve precision approaches in psychiatry and move the field forward in understanding the complexities of vulnerability phenotypes. Indeed, the variety of longitudinal dynamics and pathways underlying different psychopathological presentations in terms of age-at-onset and changes over time seems irreducibly articulated2 may have significant translational implications if integrated with the current transdiagnostic clinical staging model of mental disorders13. This would definitely catalyze a developmentally-oriented understanding of illness trajectories which is essential for both personalized risk prediction and service innovation; in particular, this integration would support a better systematization of risk factors and endophenotypic manifestations that characterize premorbid and early prodromal stages (coinciding with childhood and pre-adolescence) of underlying altered neurodevelopment trajectories headed to mental disorders. Indeed, premorbid and early prodromal stages may be developmentally viewed as characterized by a progressive functional lag starting from early unspecific cognitive/motor phenotypic expressions of underling neurobiological vulnerabilities and moving towards more specific and increasing difficulties to cope with the growing demands related to age-specific developmental tasks, especially in the social domain. The usefulness of PRS in such developmental approach to early detection of risk for mental illness appears in its potential looking at specific childhood antecedents of schizophrenia, such as premorbid cognitive development, which extricate a lifelong impact.A developmental approach to psychiatry14. First, the retrospective assessment of premorbid adjustment or estimate of premorbid IQ is intrinsically an approximation. Second, prospective studies following subjects that will develop schizophrenia since childhood , are few and with findings generally limited to relatively small final groups of schizophrenia patients. Finally, the investigation of cognitive antecedents of schizophrenia has to deal with the multifaceted nature of cognition (only roughly averaged by IQ) and whose multiple domains may have different developmental trajectories in subjects that will develop schizophrenia. For example, the findings of an early static deficit for verbal abilities and a later dynamic lag for executive controls, suggest a non-marginal intra and inter-individual heterogeneity across cognitive domains and developmental trajectories17.Cognitive development in premorbid/prodromal phases of schizophrenia is a complex phenomenon to investigate for several reasons18 that investigated the intertwine between developmental cognitive trajectories, schizophrenic symptoms, global functioning and presumed genetic load, specifically indexed by PRS for schizophrenia, cognition, educational attainment, and ADHD. Clustering current and estimated premorbid IQ, three distinct trajectories of cognitive development were identified, associated with distinct clinical and functional outcomes. Those are: stable cognitive development (37% of the sample), weakly impacted by emerging psychosis, associated with milder schizophrenic symptoms, especially in the negative domain, and relatively benign PRS profiles  - adolescent cognitive decline (44% of the sample), associated with severe schizophrenic symptoms and global impairment, due also to a higher genetic load in terms of schizophrenia and cognition PRS in comparison with controls and cognitively stable schizophrenic patients - preadolescent cognitive impairment (19% of the sample), associated with intermediate schizophrenic symptoms, fewest years of education completed and low rates of employment in adulthood, due also to a generalized unfavorable genetic load, that only in this subgroup included also education and ADHD PGSs.The combination of different PRS may therefore be a useful strategy to dig into the complex puzzle of cognitive antecedents of schizophrenia. For example, a recent cluster study14. In other terms, this strongly suggests that early cognitive impairments, as well as slower cognitive growths in the transition from childhood to adolescence17, are important early warning signals and prognostic red-flags in case of symptomatic help-seeking or familiar risk .These findings enrich our understanding of the developmental antecedents of schizophrenia and hold substantial implications for a developmentally-sensitive approach to timely detection and risk stratification of schizophrenia spectrum conditions. Moreover, they evidence how use of multiple PRS may be better suited to disentangle the genetic architecture associated with complex phenotypic modulators, such as cognition. Cognition, indeed, although not strictly related to disease-specific symptoms, certainly exerts a prognostic influence in terms of coping and global functioning11.In total, rather than a mere shortcut towards a diagnostic biomarker, PRS might carry an important and yet-to-be exploited broader translational potential. Indeed, although preliminary, studies on its early phenotypic expressivity in the general population could pave the way towards a deeper understanding of the neurodevelopmental pathogenesis of mental illness, as shown for schizophrenia7.This could be implemented through a detailed analysis of (endo)phenotypic expressions and has foreseeable implications in terms of a more accurate early staging of the risk for severe mental disorders. This would be possible integrating empirical findings from child-adolescent mental health and adult mental health along an overarching developmental conceptual framework19.In our opinion, a neuro-developmentally-informed clinical staging model of mental illness is essential to bridge together childhood neurobehavioral antecedents (presumably expressive of underlying genetic liability) and environmental/psychosocial triggers and reach a more comprehensive understanding of the longitudinal course of psychopathology


A cornerstone of human information processing is how we make decisions about incoming sensory percepts. Much of psychological science has focused on understanding how these judgements operate in skilled adult observers. While not typically the focus of this research, there is considerable variability in how adults make these judgements. Here, we review complementary computational modelling, electrophysiological data, eye-tracking and longitudinal approaches to the study of perceptual decisions across neurotypical development and in neurodivergent individuals. These data highlight multiple parameters and temporal dynamics feeding into how we become skilled adult perceptual decision makers, and which may help explain why we vary so much in how we make perceptual decisions. As skilled adult observers, we readily make accurate and fast decisions about sensory inputs of many different kinds, from dynamically changing moving stimuli to highly complex and cluttered visual scenes. Parameters underpinning optimal adult perceptual decision making have been the focus of much research in psychological science. A perhaps less well understood question is how we come to differ from each other in making such decisions. Here, we outline evidence from complementary approaches in the developmental cognitive neurosciences that point to the need to understand differences at multiple time-points of divergence in the complex dynamics leading to optimal perceptual decision making. Computational modelling, temporally sensitive neuroimaging methods and eye-tracking provide rich data on how diversity in perceptual decision making emerges, for both neurotypical and neurodivergent individuals. We begin with evidence that, when comparing children and adults, parameters feeding into perceptual decisions differ across age groups, from the onset of stimulus processing, taking moving stimuli as a central case in example. We then move onto developmental differentiation in the period during which we prepare to make perceptual decisions on the basis of our goals, prior knowledge or information recently committed to memory. We conclude by overviewing evidence from autism, dyslexia and genetic syndromes, suggesting multiple influences and routes to perceptual decision-making dynamics, both before and after the onset of incoming stimuli.1Perceptual decisions have commonly been studied in adults using random-dot motion tasks. These tasks allow the strength of sensory evidence to be manipulated precisely, and the neurophysiological correlates of sensory encoding and decisional processes have been disentangled in non-human animals or in human adults performing these tasks , making For example, Additional insights into the dynamic evolution of processes contributing to perceptual decisions can be gained from electroencephalography (EEG), due to its high temporal resolution. We adapted for children and optimised for EEG a traditional motion coherence task. One hundred white stimulus dots (described to the children as fireflies) were randomly positioned within a central square region on a black screen and moved at a speed of 6°/s. The dots had a limited lifetime of 200 ms (with randomised starting lifetimes), and dots moving outside the square stimulus region were wrapped around to the opposite side. Each trial consisted of a fixation period, a random motion period, a stimulus period, and an offset period. The fixation period, during which only the central fixation square was shown, was presented for a randomly selected duration between 800 and 1000 ms. The stimulus dots first appeared in the random motion period, during which they moved in random, incoherent directions, for a randomly selected duration between 800 and 1000 ms. In the stimulus period, a proportion of the dots moved coherently either upward or downward (described as bees to be caught by a bee-keeper), while the remainder of the dots continued to move in random directions. The stimulus period lasted until a response was made, or until 2500 ms had passed. Finally, an offset period continued the coherent stimulus presentation for a randomly selected duration between 200–400 ms. The jittered durations of the fixation, random motion and offset periods were intended to minimise expectancy effects. While children and adults performed on this motion coherence task, we collected high-density EEG data from all participants and we showed that age-related differences in motion sensitivity are accompanied by differences in both a late, sustained decision-related component and an earlier component reflecting sensory encoding  influence incoming percepts, so that our prior history guides perceptual decision making . Again, Doherty et al. (2017) combined computational approaches, eye-tracking methodology, and individual-differences measures, by asking participants to search for perceptual targets in complex visual scenes containing social or non-social distractors, and repeating exposure to those scenes and targets over blocks, to induce a learning history for their association. Eye-tracking revealed significantly more attentional capture to the social compared to the non-social distractors embedded in each scene. Critically, participants’ memory precision for target locations was poorer for social scenes compared to non-social ones. The difference between social and non-social scenes was moderated by individual differences in social anxiety, with anxious individuals remembering target locations better under conditions of social distraction than non-anxious individuals, suggesting an interplay between attentional dynamics during learning about the scenes, memory for those scenes and the characteristics of diverse observers, a point to which we return in Investigating memory-guided attention via a developmental science perspective has further nuanced our understanding of adult perceptual decisions. Doherty, Fraser et al. (2019) asked six-toten year-old children and young adults to search for targets in complex visual scenes , while eye-tracking and simple manual responses were collected. Social stimuli distracted both children and adults during visual search, and eye-tracking revealed even greater attentional capture by social distractors for children compared to adults. Intriguingly, however, children demonstrated overall better memory precision for target locations than adults. Children spent more time inspecting the whole scene before reporting target locations during the learning phase. We hypothesize that this led to greater exploration of and encoding of the full scene during the longer time inspecting it. This slower performance would normally class as less efficient search performance, but this resulted in more precise later memory, suggesting retrieval of more precise target locations either via accessing scene gist and / or landmarks within it. A further replication, combining memory precision data with eye-tracking data collected not only during the learning phase, but also the memory phase, would test this proposed mechanism more directly. Finally, when participants detected targets within visual scenes, adults were slower for targets appearing at unexpected locations within social scenes compared to non-social scenes, but this was not the case for children, again perhaps pointing to better learning of the scene as a whole. In contrast, fast processing adults focused on locating targets are very likely to have suffered from more shallow processing of the highly salient and attention-grabbing social distractors. In other words, temporal search patterns that are “slow and exploratory” for children, rather than “fast and goal-driven” for adults may reduce interference from salient distractors during the attention orienting phase. Using a similar memory-guided attention paradigm, Nussenbaum, As a whole, these complementary data suggest that the interplay between attentional biases, memory and memory-guided attention is complex, changing over developmental time and moderated by individual differences across observers. In the next section, we turn precisely to how studying neurodiversity can inform our understanding of perceptual decisions and their dynamics.3When studying neurodiversity, the complex cascade of processes feeding into perceptual decisions is even more apparent. This is because differences at multiple stages of processing can converge or distinguish individuals with diverse profiles of development. Autism, which affects social communicative and non-social behaviours, and dyslexia, which affects reading ability, are distinct conditions that have both been linked to atypical motion sensitivity . Multi-mDespite these similar patterns in EEG activity for autistic and dyslexic children, diffusion modelling studies combined with response-locked EEG indices have uncovered differences in processing between autistic and dyslexic children. Dyslexic children show reduced accumulation of motion evidence compared to typically developing children, across two motion tasks that differed in their requirements for segregating signal from noise . These dOf note, further valuable insights can come from neurodivergent individuals for whom symptoms of autism and attention differences cluster together. Fragile X syndrome (FXS) is the most common genetically identified and inherited monogenic syndrome associated with a high prevalence of autistic and ADHD symptoms . By tracking autism and ADHD symptoms longitudinally over the course of three years across a diverse group of children and teenagers with FXS, Doherty et al. (2020) found that individual variation in ADHD symptoms predicted later individual variation in autism symptoms, bolstering the need to investigate more precisely how attention, activity levels and autistic characteristics interact over developmental time. Indeed, In their entirety, complementary multi-method data about how neurodivergent children and young people make perceptual decisions converge in suggesting that there are multiple ways in which observers can differ over the timeline leading to perceptual decisions: from preparation, to processing of stimuli and decision-making, as well as in the short-term prior history and longitudinal change. Of note, we began by describing how a decision-theoretic framework inform can help disentangle distinct contributors to perceptual choice, and how these parameters manifest in temporally distinguishable differences between neurotypical and neurodivergent children . A parallel set of findings points again to dynamics, suggesting that preparatory and memory-dependent dynamics influence perceptual decisions differently across ages. However, the two literatures have not yet been bridged: i.e., to our knowledge developmental scientists have not yet tested whether pre-stimulus dynamics  change post-stimulus decisional parameters , rather than simply affect perceptual choices. What is also not known is whether preparatory dynamics influence decisional parameters differently in neurotypical and neurodivergent children. Future research could integrate approaches to pre-stimulus and pre-decision dynamics, for both neurodivergent and neurotypical development from childhood into adulthood.4We have reviewed evidence that multiple complex parameters contribute to perceptual decisions, and that these parameters can differ in informative ways across development and with neurodiversity. A better understanding of the developmental processes involved may help us to in turn understand the perceptual decisions made by skilled adult observers, and in particular, why there is considerable variability in how people make perceptual decisions.


An imbalance between these two processes lies at the basis of multiple neuropathologies. Recent evidence has highlighted the importance of glia-neuron interactions in the synaptic unit, emphasized by glial phagocytosis of synapses and local excretion of inflammatory mediators. These findings warrant a closer look into the molecular basis of cell-signaling pathways in the different brain cells that are related to synaptic plasticity. In neurons, intracellular second messengers, such as cyclic guanosine or adenosine monophosphate , are known mediators of synaptic homeostasis and plasticity. Increased levels of these second messengers in glial cells slow down inflammation and neurodegenerative processes. These multi-faceted effects provide the opportunity to counteract excessive synapse loss by targeting cGMP and cAMP pathways in multiple cell types. Phosphodiesterases (PDEs) are specialized degraders of these second messengers, rendering them attractive targets to combat the detrimental effects of neurological disorders. Cellular and subcellular compartmentalization of the specific isoforms of PDEs leads to divergent downstream effects for these enzymes in the various central nervous system resident cell types. This review provides a detailed overview on the role of PDEs and their inhibition in the context of glia-neuron interactions in different neuropathologies characterized by synapse loss. In doing so, it provides a framework to support future research towards finding combinational therapy for specific neuropathologies.Synapses are the functional units of the brain. They form specific contact points that drive neuronal communication and are highly plastic in their strength, density, and shape. A carefully orchestrated balance between synaptogenesis and synaptic pruning,  Synapses are contact points between neurons that allow them to communicate with each other and, hence, are vital to proper brain function. The amount of synapses is strictly and dynamically regulated throughout the human lifespan by constant turnover of synapses. Regular formation of synapses is offset by the elimination of synapses that are too weak or in excess The central nervous system (CNS) consists of different cell types with dedicated functions, i.e. protein kinase A [PKA] and PKG, respectively) close to their substrates (cAMP and cGMP), allowing an adequate physiological response of the cell to a signal. Despite the signaling contribution of cGMP to neuroplasticity, GKAP/PKG signalosomes are not well characterized yet. This review will focus on AKAP/cAMP complexes. Extensive research has demonstrated that elevating cAMP and cGMP levels can drive the CNS towards a neuroprotective environment to prevent damage Synapse formation and elimination rely heavily on second messengers as effectors Table 1) and interactions with mediators of phosphorylation. The different genes  are unique in terms of their genomic organization, including the use of multiple promoters. Divergent isoforms  exist owing to the existence of multiple promoters and the influence of alternative splicing. Isoforms of PDE4, for instance, can be classified into long, short, or supershort, based on the presence of upstream conserved regions (UCR's). Long isoforms have two of these UCR's, short isoforms have one, and the supershort has a truncated version of one. The presence of different PDE transcripts and their association with anchoring proteins in distinct pathways of cell signaling throughout the CNS leads to the widespread effects of PDE-mediated signaling pathways. These biochemical differences have also comprehensively been elucidated in research studies using C. elegansThe physiology of PDEs carries a well-established diversity: 21 genes have been identified, which code for proteins that differ vastly in their regulatory properties and spatiotemporal organization. The 21 genes of the PDE superfamily can be distinguished by their catalytic unit and are grouped in 11 different families (PDE1-PDE11) based on protein structure and regulatory domains. These protein structures affect substrate selectivity  synapses. Glutamatergic synapses rely on both metabotropic (mGluRs) and ionotropic glutamate receptors, such as kainite receptors, N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, of which the latter is responsible for baseline neurotransmission. Importantly, the synapse type dictates its structure. Inhibitory synapses (e.g. GABAergic) are mostly formed directly on dendritic shafts. Excitatory synapses (e.g. glutamatergic) are usually formed by using dendritic spines, which are small membrane protrusions from dendritic shafts, creating a postsynaptic partner for excitatory neurons Synapses can differ according to the neurons with which they are made up. Among chemical synapses, two types can be distinguished, Apart from plasticity that is inherent to neuronal functioning, the effect of interaction of synapses with other, external, factors should not be overlooked. Glial cells, responsible for homeostatic balance and support of the neuronal circuit, play a major role in plasticity. Apart from indirectly changing the micro-environment, glial cells have emerged as direct regulators of synapse maintenance and elimination. Endfeet of astrocytes converge on neuronal contact sites to create the tripartite synapse Table 1) The importance of glial cells in synaptic elimination has already been established i.e. from early development up to childhood and during adolescence. Synaptic elimination during development is well-documented, as observed in the developing neuromuscular junction in rodents. Aside from the neuromuscular junction, experiments have highlighted that synapse elimination also occurs in sensory and executive circuits of the brain. As such, synaptic elimination represents a key developmental process in the cerebellum, cortex, thalamus, and the hippocampus Loss of spines and synapse elimination is critical both in the primary and secondary phase of human brain circuit formation, As synapse elimination occurs in different stages of life, an important distinction has to be made between normal and pathological aging. Medical advances and public health efforts have led to a substantial increase in the percentage of older adults in the general population. Aging remains an underlying risk factor for many neurodegenerative diseases and is often accompanied by notably deteriorating cognitive capacities in vitro experiments or in in vivo animal model studies. However, to date, few PDE inhibitors have bridged the translational gap to become an approved therapy in the area of neurological disorders. Alzheimer's research, specifically, has looked into the potential of PDE inhibitors quite extensively An important challenge of pharmacological inhibition of PDEs is the ability to translate preclinical work to therapeutics in humans. As illustrated below to a greater extent, the proven beneficial effects of PDE inhibition have been established in The brain circuitry is known to undergo many neuronal changes throughout the human lifespan Synapses are subject to activity-dependent competition. Active synaptic connections are retained, while poorly used synapses are prone to elimination. Furthermore, coincident activity of pre- and postsynaptic compartments leads to synapse strengthening. This dynamic nature of synapse strengthening or elimination enables a high degree of plasticity, which is crucial in learning and memory processes. Accordingly, synapse elimination would promote plasticity as long as it is appropriately targeted to rather inactive synapses. In neurodegenerative diseases, a decline in plasticity can be observed due to deficient strengthening and excessive elimination of synapses, even for adequately used synapses. Importantly, the increased inflammatory state in the aging and neurodegenerative brain, mediated by overactive astrocytes, microglia, and macrophages, poses a challenge for the maintenance and strengthening of these synapses. As such, excessive and non-specific synapse loss in neurodegeneration can be limited by promoting synaptic strengthening and dampening inflammatory signaling.de novo protein synthesis -mediated transcription e.g., by increases in scaffolding proteins such as PSD95 e.g., owing to more membrane-bound AMPA receptors e.g., via brain-derived neurotrophic factor (BDNF) Activity-dependent synapse strengthening is tightly regulated by and dependent on cyclic nucleotide signaling cascades. Upon receptor activation on the postsynaptic neuron, calcium influx and G-protein coupled receptor stimulation promotes the synthesis of cGMP and cAMP. The second messengers cGMP and cAMP can then, either directly or via downstream effectors, modulate both transient and prolonged plasticity changes et al.i.e., enhancing plasticity and reducing inflammation) of PDE4 inhibition, this therapeutic strategy has been investigated in a variety of neurodegenerative disorders to protect neurons and their functional synapses e.g., headaches, diarrhea, and nausea) In addition to the modulation of neuroplasticity effects, cyclic nucleotides also affect neuroinflammatory processes In vitro and in vivo studies demonstrated that LRRK2 is responsible for the localization of cAMP/PKA signaling in dendritic spines and negatively regulates cAMP/PKA signaling during synaptogenesis. In particular, LRRK2 knock-out mice exhibit increased PKA phosphorylation of AMPA receptors, leading to abnormal dendrite morphology. Thus, LRRK2/cAMP complexes play a dual role, protecting neuronal cells from inflammation and balancing intracellular signaling for the healthy development of dendrites during synaptogenesis. Furthermore, research has shown that LRRK2 is associated with Parkinson's disease cAMP compartmentalization plays a vital role in synaptic plasticity. The AKAP5-PDE4D5 complex, which is attached to the postsynaptic membrane, regulates cAMP signaling and plays a crucial role in learning and memory by facilitating activation of AMPA receptors in response to a signal Ample research has detailed the active role of neurons in phagocytic signaling. For instance, neurophagy, the phagocytosis of live neurons and synapses by glia, is dependent on active intercellular signaling. The neuronal cell surface displays various “eat-me” signals to attract and activate phagocytic glia et al.Microglia develop from erythromyeloid progenitor cells. During early development, they travel via the bloodstream and infiltrate the brain Microglia also regulate the inflammatory response by producing cytokines, such as tumor necrosis factor alpha (TNF-α), interleukin-1 beta (IL-1β), chemokines, free radicals, and nitric oxide (NO) in vivo  in microglia, while sildenafil has been found to upregulate chitinase 3-like 3 (YM-1), skewing them towards an anti-inflammatory phenotype in vivoPDE4 inhibitors (including rolipram) and a PDE4D-negative allosteric modulator (D158681) In vivo pre- and postnatal microglial depletion or perturbation models reveals the essential role for microglia in synapse formation, refinement, and elimination . Microglial cAMP and cGMP have also been shown to be critical for microglial surveillance of the brain parenchyma and, therefore, rapid and subtle manipulation of cAMP and cGMP levels can dramatically affect their role in synaptic elimination. The addition of the non-selective, also called pan-PDE blocker, IBMX, prevents the breakdown of cAMP and triggers a fast retraction of microglial processes in situ, leading to reduced elimination. Specific blocking of PDE3B, whose expression is highly enriched in microglia, has a similar effect, suggesting that intracellular cAMP and cGMP levels regulate the morphology and sensing mechanism of microglia In addition to their protective functions, microglia are critical cells in overall brain maintenance. Both during development and homeostasis, microglia actively survey and shape the brain parenchyma by physically monitoring neurons and synapses ex vivo live-imaging has not found evidence of active phagocytosis of complete synapses by microglia An important point to raise is that Synaptic elimination involves many cues that promote and inhibit the detection and removal of specific synapses , chemokine receptors, and TREM2) in vitro co-cultures of monocyte-derived macrophages and neurons have further emphasized the possible involvement of these macrophages with regards to synapse refinements, as synapse material was found present within these macrophages The central myeloid cell population of the CNS is composed of parenchymal microglia and non-parenchymal macrophages, including perivascular macrophages, meningeal macrophages, macrophages of the choroid plexus and blood-borne monocytes In vivo studies further confirmed the destructive nature of the infiltrated macrophages, since the level of macrophage infiltration in aged rats correlated with reduced synaptic functioning During aging, blood-borne monocytes infiltrate the brain parenchyma, where they differentiate into microglia-like monocyte-derived macrophages in vitro, dramatic changes can be observed with regards to PDE expression Even though the exact role of non-parenchymal macrophages remains inconclusive, several current studies have aimed at skewing specific macrophage-mediated responses to resolve neurodegenerative disease. One strategy to regulate macrophage functions is to alter intracellular levels of second messengers by inhibiting specific PDEs. To understand which type of PDE inhibition could be beneficial in particular processes, differences in PDE expression profiles have been mapped. Interestingly, when peripheral monocytes differentiate towards macrophages in vitro, only a minor decrease in purinergic receptor P2X7 gene expression was seen in schizophrenia material upon pro-inflammatory LPS stimulation The importance of synaptic maintenance and preservation is especially highlighted in schizophrenia. In schizophrenic patients, an increase in the absolute number of circulating peripheral blood monocytes was found, whereas an increase of macrophages was observed in the cerebrospinal fluid of schizophrenia patients during an acute psychotic episode in vitro and in vivo studies have showed an increased capacity of these monocyte-derived macrophages to remove Aβ fibrils, a process mediated by intracellular CD36/early endosomal antigen-1 (EEA1) early endosomal proteolysis in vivoOwing to their phagocytic capacity, macrophages have been extensively investigated for their possible neuroprotective potential in AD, as they may regulate Aβ clearance Understanding isoform-specific PDE expression changes can offer insights into PDE inhibitor development as a therapeutic strategy to alter macrophage-mediated responses in the CNS. As such, PDE inhibitors can be beneficial in multiple CNS disorders, either by changing the phagocytic capacity of macrophages or by downregulating their pro-inflammatory markers and therefore resolving neuroinflammation. Besides PDE4, PDE1B2 suppression has been studied for its effect on macrophages. When PDE1B2 was specifically suppressed, macrophages showed an increased phagocytic ability and enhanced cell spreading There is little information available about the compartmentalization of second messengers within CNS macrophages. Evidence has been found to show that AKAP10 (AKAP-D) and AKAP95 regulate secretion of anti-inflammatory cytokines IL-10, IL-6, and TNF-α through cAMP/PKA signaling in alveolar macrophages in vitroAstrocytes are the most abundant cells within the CNS. Their supportive and protective role renders them indispensable in normal brain functioning. As such, astrocytes are involved in extracellular matrix (ECM) homeostasis, neurotransmitter recycling, neuroplasticity, and many other processes. Their particular contribution to synaptic formation, maintenance, and elimination has become more appreciated over the past decades. Astrocytes secrete synaptogenic factors, such as thrombospondins, which are required during synaptic formation and act to strengthen functional synapses et al. showed that astrocytes express phagocytic receptors, such as MER Proto-Oncogene, Tyrosine Kinase (MERTK) and multiple epidermal growth factor like domains 10 (MEGF10), which are responsible for synapse targeting and elimination In addition to microglia, astrocytes have been shown to be involved in synaptic elimination. A study by Chung in vitro and in vivoReactive astrocytes have also been shown to be closely associated with amyloid plaques in AD brains and were found to internalize Aβ both i.e., superoxide dismutase 1 (SOD1)- and huntingtin (htt)-mediated, respectively, show defective astrocytic glutamate transporters, eventually leading to extracellular glutamate accumulation and neuronal death through excitotoxicity in vivoAstrocytes target both excitatory and inhibitory synapses, yet the balance varies during different developmental stages. In the first phase of postnatal development, more excitatory synapses are engulfed, likely owing to the higher rate of synaptogenesis in this phase. This observation shows that astrocytes play a pivotal role in maintaining the E/I equilibrium Oligodendrocytes are indispensable in CNS functioning. In the case of synapse loss, however, their role is not yet fully understood. The supportive, seemingly static role of oligodendrocytes reaches well beyond their prominent role as myelinating cells of the CNS; they are active participants in cell-signaling pathways. The oligodendrocytic processes are in intimate contact with neurons at both pre- and postsynaptic structures, facilitating nutritional and structural support for synapses Oligodendrocytes are the myelinating glia of the brain. Though proven to be indispensable for brain functioning, to the best of our knowledge, they have not been studied extensively in the context of synapse development, maintenance, or plasticity. As previously illustrated, glial-secreted factors are of undeniable importance for synaptic maturation and maintenance. Notably, in the developing brain, oligodendrocytes actively participate in synaptic plasticity through BDNF signaling, promoting neuronal survival and plasticity by inducing LTP Studies looking into the involvement of oligodendrocyte precursor cells (OPCs) have found evidence of them receiving signals from axons for myelination in an activity-dependent manner via glutamatergic signaling. The abundantly present AMPA- and NMDA-type glutamate receptors mediate OPC proliferation and migration or myelination, respectively PDEs have been at the center of many investigative strategies aimed at understanding various diseases. Increased understanding of signaling cascades surrounding specific PDE isoforms has uncovered their potential as therapeutic targets. As non-selective inhibition often proves ineffective or is accompanied by adverse effects, only a small number of PDE inhibitors have translated to the clinic, and many inhibitors still require validation for clinical neuromodulation Elevation of cyclic nucleotide levels in astrocytes ameliorates neuromodulatory processes, contributing to a suitable environment for synaptic plasticity. In addition to astrocytes, microglia are the other neuroglial cells directly interacting with synapses. They influence not only elimination, but also the formation and protection of synapses. This influence is exerted during development and learning, as well as in aging and neurodegeneration. In the latter case, when neuroinflammation is widespread, PDE inhibition has proven useful in counteracting the activation of microglia, limiting the effect of inflammatory signaling. Additionally, the phagocytic capacity of astrocytes and microglia contributes to the elimination of synapses via its focal clearance. Comparison of astrocytic and microglial phagocytosis addresses an interesting knowledge gap, as it remains unclear if and, if so, how neural activity controls the rate of astrocyte-mediated synapse phagocytosis, whether astrocytes and microglia phagocytose different synapse types or circuits, and which different 'eat me signals' are involved Notably, the effects of PDE inhibition have a direct modulatory effect on neurons, contributing to synaptic plasticity and neuroprotection. Both transient and lasting changes on plasticity can be achieved by targeting neurons, ultimately strengthening the synaptic network. The direct effects of the inflammatory environment on neurons can be affected by PDE inhibition. Previous work digging deeper into targeting isoforms of PDEs has focused largely on neurons, yet an exciting avenue might be to pursue glial cells. The effects of isoform compartmentalization are readily apparent in various forms of synaptic plasticity in neurons, so finding out to what extent varying isoforms alter glial cell functioning might prove valuable to understanding neurodegeneration. An interesting avenue that has been the focus of many research labs is the neuronal expression of intercellular signaling molecules that can activate surrounding glial cells. Many of these signals have second messengers lying downstream or upstream to PDE-directed pathways, rendering them vulnerable to PDE signaling In closing, the role of glial cells and glia-neuron communications has gained increasing interest as a driving factor behind many diseases. Enhancement of both cAMP and cGMP signaling can successfully promote synapse strengthening and diminish inflammatory signaling, as is evident by the use of a variety of PDE inhibitors. As such, PDE inhibition has potential as a therapeutic approach to make neurons and their synapses more resilient to (disease-induced) glia-mediated elimination. The usefulness of PDE inhibitors is not limited to protecting neurons, however. By actively altering cell signaling in glial cells, a more direct approach can also be pursued. Recent advances in understanding different neuropathologies have opened up interesting avenues towards personalized medicine. As summarized in this review, the specific expression pattern of PDEs in different cell types allows targeted treatment strategies. Expanding on this notion, the targeting of isoform-specific PDE signatures per cell type may prevent neuroinflammation, while promoting synaptic plasticity in divergent pathologies. Because of this, the holistic impact of PDE inhibition can be beneficial to the entire synaptic unit. Consequently, combination therapy consisting of inhibitors targeting multiple PDEs, over multiple cell types, paves the way towards personalized medicine. This underlying potential solidifies that PDE inhibitors remain a viable strategy, yet require additional research to reach their full potential. Although the use of PDE inhibitors can lead to adverse side effects, targeting of specific isoforms holds promise to circumvent these unwanted effects. By determining the predominant isoforms of PDEs in fundamental pathways of neurodegenerative diseases, a deeper understanding of their causative mechanisms can be achieved. The additive effect of combining multiple isoform-specific drugs into pathology-specific therapy holds promise to finally unlock the full potential of PDE inhibitors.