The motor profile of obsessive-compulsive rituals: psychopathological and evolutionary implications.

BACKGROUND: Studies investigating obsessive-compulsive disorder from an ethological approach have highlighted a specific motor pattern of compulsive rituals with respect to corresponding ordinary behaviors. Particularly, compulsive motor profile is built through the repetition of acts, with prevalence of nonfunctional ones and redirection of attention to its basic structural units. These formal features would characterize ritual behavior throughout evolution, from nonhuman animals to human cultures. However, no study to date has investigated a possible relationship between such motor profile and underlying psychopathology. Therefore, the first objective of the study was to confirm previous findings on a larger sample size of obsessive patients; the second objective was to elucidate whether motor profile might be associated with obsessive-compulsive psychopathology and/or prepsychotic symptoms of schizophrenia. METHODS: Twenty-one obsessive-compulsive outpatients provided a videotape of their rituals. An equal number of healthy controls, matched for sex and age, were registered for corresponding ordinary acts. Obsessive patients were administered the Yale-Brown Obsessive-Compulsive Scale, the Brown Assessment of Beliefs Scale, the Hamilton Rating Scale for Depression, and the Frankfurt Complaint Questionnaire. RESULTS: The results of the present study confirm that ritual compulsions present a specific motor structure characterized by repetition of both functional and nonfunctional acts and their longer duration. Such a motor pattern is independent from obsessive-compulsive psychopathology, whereas it results specifically associated with prepsychotic symptoms of schizophrenia. CONCLUSIONS: We argue that this association may reflect the adaptive significance of ritual behavior across evolution, that is, its homeostatic function in conditions of unpredictability.

Quo Vadis Psychiatry? Why It Is Time to Endorse Evolutionary Theory.

ABSTRACT: In recent decades, psychiatry and the neurosciences have made little progress in terms of preventing, diagnosing, classifying, or treating mental disorders. Here we argue that the dilemma of psychiatry and the neurosciences is, in part, based on fundamental misconceptions about the human mind, including misdirected nature-nurture debates, the lack of definitional concepts of "normalcy," distinguishing defense from defect, disregarding life history theory, evolutionarily uninformed genetic and epigenetic research, the "disconnection" of the brain from the rest of the body, and lack of attention to actual behavior in real-world interactions. All these conceptual difficulties could potentially benefit from an approach that uses evolutionary theory to improve the understanding of causal mechanisms, gene-environment interaction, individual differences in behavioral ecology, interaction between the gut (and other organs) and the brain, as well as cross-cultural and across-species comparison. To foster this development would require reform of the curricula of medical schools.

Conditional Inactivation of Limbic Neuropeptide Y-1 Receptors Increases Vulnerability to Diet-Induced Obesity in Male Mice.

NPY and its Y1 cognate receptor (Y1R) have been shown to be involved in the regulation of stress, anxiety, depression and energy homeostasis. We previously demonstrated that conditional knockout of Npy1r gene in the excitatory neurons of the forebrain of adolescent male mice (Npy1rrfb mice) decreased body weight growth and adipose tissue and increased anxiety. In the present study, we used the same conditional system to examine whether the targeted disruption of the Npy1r gene in limbic areas might affect susceptibility to obesity and associated disorders during adulthood in response to a 3-week high-fat diet (HFD) regimen. We demonstrated that following HFD exposure, Npy1rrfb male mice showed increased body weight, visceral adipose tissue, and blood glucose levels, hyperphagia and a dysregulation of calory intake as compared to control Npy1r2lox mice. These results suggest that low expression of Npy1r in limbic areas impairs habituation to high caloric food and causes high susceptibility to diet-induced obesity and glucose intolerance in male mice, uncovering a specific contribution of the limbic Npy1r gene in the dysregulation of the eating/satiety balance.

Effects of Prenatal Exposure to a Low-Dose of Bisphenol A on Sex Differences in Emotional Behavior and Central Alpha2-Adrenergic Receptor Binding.

Prenatal exposure to bisphenol A (BPA) influences the development of sex differences neurologically and behaviorally across many species of vertebrates. These effects are a consequence of BPA's estrogenic activity and its ability to act as an endocrine disrupter even, at very low doses. When exposure to BPA occurs during critical periods of development, it can interfere with the normal activity of sex steroids, impacting the fate of neurons, neural connectivity and the development of brain regions sensitive to steroid activity. Among the most sensitive behavioral targets of BPA action are behaviors that are characterized by a sexual dimorphism, especially emotion and anxiety related behaviors, such as the amount of time spent investigating a novel environment, locomotive activity and arousal. Moreover, in some species of rodents, BPA exposure affected males' sexual behaviors. Interestingly, these behaviors are at least in part modulated by the catecholaminergic system, which has been reported to be a target of BPA action. In the present study we investigated the influence of prenatal exposure of mice to a very low single dose of BPA on emotional and sexual behaviors and on the density and binding characteristics of alpha2 adrenergic receptors. Alpha2 adrenergic receptors are widespread in the central nervous system and they can act as autoreceptors, inhibiting the release of noradrenaline and other neurotransmitters from presynaptic terminals. BPA exposure disrupted sex differences in behavioral responses to a novel environment, but did not affect male mice sexual behavior. Importantly, BPA exposure caused a change in the binding affinity of alpha2 adrenergic receptors in the locus coeruleus and medial preoptic area (mPOA) and it eliminated the sexual dimorphism in the density of the receptors in the mPOA.

What is stressful for females? Differential effects of unpredictable environmental or social stress in CD1 female mice.

Stressful life events are a major factor in the etiology of several diseases, such as cardiovascular, inflammatory and psychiatric disorders (i.e., depression and anxiety), with the two sexes greatly differing in vulnerability. In humans and other animals, physiological and behavioral responses to stress are strongly dependent on gender, and conditions that are stressful for males are not necessarily stressful for females. Hence the need of an animal model of social chronic stress specifically designed for females. In the present study we aimed to compare the effects of two different chronic stress procedures in female mice, by investigating the impact of 4weeks of nonsocial unpredictable, physical stress by the Chronic Mild Stress paradigm (CMS; Exp.1) or of Social Instability Stress (SIS; Exp.2) on physiological, endocrine and behavioral parameters in adult female mice. CMS had a pronounced effect on females' response to novelty (i.e., either novel environment or novel social stimulus), body weight growth and hormonal profile. Conversely, 4weeks of social instability did not alter females' response to novelty nor hormonal levels but induced anhedonia. Our findings thus showed that female mice were more sensitive to nonsocial stress due to unpredictable physical environment than to social instability stressors. Neither of these stress paradigms, however, induced a consistent behavioral and physiological stress response in female mice comparable to that induced by chronic stress procedures in male mice, thus confirming the difficulties of developing a robust and validated model of chronic psychosocial stress in female mice.

Current Knowledge on Endocrine Disrupting Chemicals (EDCs) from Animal Biology to Humans, from Pregnancy to Adulthood: Highlights from a National Italian Meeting.

Wildlife has often presented and suggested the effects of endocrine disrupting chemicals (EDCs). Animal studies have given us an important opportunity to understand the mechanisms of action of many chemicals on the endocrine system and on neurodevelopment and behaviour, and to evaluate the effects of doses, time and duration of exposure. Although results are sometimes conflicting because of confounding factors, epidemiological studies in humans suggest effects of EDCs on prenatal growth, thyroid function, glucose metabolism and obesity, puberty, fertility, and on carcinogenesis mainly through epigenetic mechanisms. This manuscript reviews the reports of a multidisciplinary national meeting on this topic.

Correction to: Parma consensus statement on metabolic disruptors.

CORRECTION: After publication of the article [1], it has been brought to our attention that the thirteenth author of this article has had their name spelt incorrectly. In the original article the spelling "Laura Rizzir" was used. In fact the correct spelling should be "Laura Rizzi".

Parma consensus statement on metabolic disruptors.

A multidisciplinary group of experts gathered in Parma Italy for a workshop hosted by the University of Parma, May 16-18, 2014 to address concerns about the potential relationship between environmental metabolic disrupting chemicals, obesity and related metabolic disorders. The objectives of the workshop were to: 1. Review findings related to the role of environmental chemicals, referred to as "metabolic disruptors", in obesity and metabolic syndrome with special attention to recent discoveries from animal model and epidemiology studies; 2. Identify conclusions that could be drawn with confidence from existing animal and human data; 3. Develop predictions based on current data; and 4. Identify critical knowledge gaps and areas of uncertainty. The consensus statements are intended to aid in expanding understanding of the role of metabolic disruptors in the obesity and metabolic disease epidemics, to move the field forward by assessing the current state of the science and to identify research needs on the role of environmental chemical exposures in these diseases. We propose broadening the definition of obesogens to that of metabolic disruptors, to encompass chemicals that play a role in altered susceptibility to obesity, diabetes and related metabolic disorders including metabolic syndrome.

The Conflict between Regulatory Agencies over the 20,000-Fold Lowering of the Tolerable Daily Intake (TDI) for Bisphenol A (BPA) by the European Food Safety Authority (EFSA).

BACKGROUND: The European Food Safety Authority (EFSA) recommended lowering their estimated tolerable daily intake (TDI) for bisphenol A (BPA) 20,000-fold to 0.2 ng/kg body weight (BW)/day. BPA is an extensively studied high production volume endocrine disrupting chemical (EDC) associated with a vast array of diseases. Prior risk assessments of BPA by EFSA as well as the US Food and Drug Administration (FDA) have relied on industry-funded studies conducted under good laboratory practice protocols (GLP) requiring guideline end points and detailed record keeping, while also claiming to examine (but rejecting) thousands of published findings by academic scientists. Guideline protocols initially formalized in the mid-twentieth century are still used by many regulatory agencies. EFSA used a 21st century approach in its reassessment of BPA and conducted a transparent, but time-limited, systematic review that included both guideline and academic research. The German Federal Institute for Risk Assessment (BfR) opposed EFSA's revision of the TDI for BPA. OBJECTIVES: We identify the flaws in the assumptions that the German BfR, as well as the FDA, have used to justify maintaining the TDI for BPA at levels above what a vast amount of academic research shows to cause harm. We argue that regulatory agencies need to incorporate 21st century science into chemical hazard identifications using the CLARITY-BPA (Consortium Linking Academic and Regulatory Insights on BPA Toxicity) nonguideline academic studies in a collaborative government-academic program model. DISCUSSION: We strongly endorse EFSA's revised TDI for BPA and support the European Commission's (EC) apparent acceptance of this updated BPA risk assessment. We discuss challenges to current chemical risk assessment assumptions about EDCs that need to be addressed by regulatory agencies to, in our opinion, become truly protective of public health. Addressing these challenges will hopefully result in BPA, and eventually other structurally similar bisphenols (called regrettable substitutions) for which there are known adverse effects, being eliminated from all food-related and many other uses in the EU and elsewhere. https://doi.org/10.1289/EHP13812.

The effects of bisphenol A on emotional behavior depend upon the timing of exposure, age and gender in mice.

Experimental evidence suggests that endocrine-disrupting chemicals (EDCs) can permanently disrupt the development of sexually dimorphic behaviors and the structure of sexually dimorphic areas of the brain. EDC exposure has different effects depending on diverse factors, such as the timing and dose of the exposure, the maternal environment and the individual's age and sex. Among EDCs, bisphenol A (BPA) is one of the most studied because of its extensive use, which ranges from dentistry to food/drink packaging. In the present study, we aimed to investigate the behavioral effects of developmental exposure to a low dose of BPA with respect to the timing of the exposure, maternal environment, sex and age at testing. Starting from the last week of pregnancy to the first postpartum week, dams spontaneously drank either corn oil (control group) or a solution containing BPA (10 µg/kg bw/day). At birth, the litters were cross-fostered to different dams to differentiate among the effects of pre- and postnatal exposure. Pre- and postnatally exposed offspring underwent three diverse experimental paradigms for anxiety-related behaviors: as juveniles, a novelty test and at adulthood, both the free exploratory open field and elevated plus maze tests. At both testing ages, pre- and postnatally exposed females showed evidence of increased anxiety and were less prone to explore a novel environment relative to the control females, showing a behavioral profile more similar to control males than females. In this study, the direction of the behavioral changes was affected similarly by the pre- and postnatal exposures, resulting in a disruption of these sexually dimorphic behaviors, although with a greater effect associated with postnatal exposure primarily in females. Our findings indicate that non-reproductive, sexually dimorphic behaviors are sensitive to endocrine disruption during critical developmental periods-particularly the highly critical early neonatal stage. Combined with previous research, our study provides further evidence of the potential risks that even low doses of EDCs may pose to humans, with fetuses and infants being highly vulnerable.

Characterization of a novel peripheral pro-lipolytic mechanism in mice: role of VGF-derived peptide TLQP-21.

The peptides encoded by the VGF gene are gaining biomedical interest and are increasingly being scrutinized as biomarkers for human disease. An endocrine/neuromodulatory role for VGF peptides has been suggested but never demonstrated. Furthermore, no study has demonstrated so far the existence of a receptor-mediated mechanism for any VGF peptide. In the present study, we provide a comprehensive in vitro, ex vivo and in vivo identification of a novel pro-lipolytic pathway mediated by the TLQP-21 peptide. We show for the first time that VGF-immunoreactivity is present within sympathetic fibres in the WAT (white adipose tissue) but not in the adipocytes. Furthermore, we identified a saturable receptor-binding activity for the TLQP-21 peptide. The maximum binding capacity for TLQP-21 was higher in the WAT as compared with other tissues, and selectively up-regulated in the adipose tissue of obese mice. TLQP-21 increases lipolysis in murine adipocytes via a mechanism encompassing the activation of noradrenaline/ß-adrenergic receptors pathways and dose-dependently decreases adipocytes diameters in two models of obesity. In conclusion, we demonstrated a novel and previously uncharacterized peripheral lipolytic pathway encompassing the VGF peptide TLQP-21. Targeting the sympathetic nerve-adipocytes interaction might prove to be a novel approach for the treatment of obesity-associated metabolic complications.

Disembodiment and Language in Schizophrenia: An Integrated Psychopathological and Evolutionary Perspective.

Different hypotheses have flourished to explain the evolutionary paradox of schizophrenia. In this contribution, we sought to illustrate how, in the schizophrenia spectrum, the concept of embodiment may underpin the phylogenetic and developmental pathways linking sensorimotor processes, the origin of human language, and the construction of a basic sense of the self. In particular, according to an embodied model of language, we suggest that the reuse of basic sensorimotor loops for language, while enabling the development of fully symbolic thought, has pushed the human brain close to the threshold of a severe disruption of self-embodiment processes, which are at the core of schizophrenia psychopathology. We adopted an inter-disciplinary approach (psychopathology, neuroscience, developmental biology) within an evolutionary framework, to gain an integrated, multi-perspectival model on the origin of schizophrenia vulnerability. A maladaptive over-expression of evolutionary-developmental trajectories toward language at the expense of embodiment processes would have led to the evolutionary "trade-off" of a hyper-symbolic activity to the detriment of a disembodied self. Therefore, schizophrenia psychopathology might be the cost of long-term co-evolutive interactions between brain and language.

The association between childhood trauma and motor structure in obsessive-compulsive rituals: An ethological and evolutionary approach.

OBJECTIVE: Ethological models have highlighted a specific motor structure of compulsions in obsessive-compulsive disorder (OCD), based on the rigid repetitions of acts, and with the adaptive significance of facing unpredictable conditions. Such an evolutionary mechanism might explain the robust association between childhood traumatic experiences (CTEs) and OCD. However, a relationship between CTEs and the motor structure of compulsions has not been investigated yet. The first objective of the study was to confirm a specific motor structure of OCD compulsions with respect to control behaviors; the second objective was to assess a possible association between the motor structure of compulsions and CTEs severity. METHOD: Thirty-two OCD outpatients (13 female, Mage = 44.50 years, SE = 19.71) and 27 healthy controls (10 female, Mage = 37.62 years, SE = 16.20), matched for sex and age, provided a videotape of their compulsions and corresponding ordinary acts, respectively. Behavior was scored with the software "Observer." Participants were administered the Yale-Brown Obsessive Compulsive Scale and the Childhood Trauma Questionnaire. A dependent t test was used to compare the motor structure of behavior between the groups; Pearson's correlations to investigate associations between motor parameters and CTEs. RESULTS: Compulsions showed a specific motor structure due to the repetition of functional and nonfunctional acts. CTEs severity was especially associated with the repetition of functional acts, independently from OCD severity. CONCLUSION: Our findings, in confirming a peculiar motor structure for OCD compulsions, hint for the first time at a link between CTEs and compulsive repetition of functional acts, which would represent a plastic developmental response to CTEs unpredictability. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Non-invasive administration of poractant-α in neonatal respiratory distress syndrome via a supraglottic device in the clinical practice in a second level neonatal unit: comparison of LMA® vs iGel® devices.

Non-invasive pulmonary surfactant (SF) administration for neonatal respiratory distress syndrome (NRDS) is a development of administration of SF. Administration of SF via a supraglottic device (SGD) has been shown to be effective. Here the results of administration of SF in NRDS in infants requiring oxygen and nasal-CPAP (n-CPAP) via two types of SGDs, LMA® vs iGel®, in a second level Neonatal Unit are reported in a retrospective study. Results - Fourteen infants in the LMA®Group were matched with 21 comparable infants in the iGel® Group (g.a. ≥30 wks and b.w. ≥ 1,500 gr) presenting NRDS with fraction of inspired oxygen (FiO2) ≥ 0.25 - 0.6, requiring n-CPAP. All infants presented a significant improvement of PaO2/FiO2 ratio that was seen earlier in the iGel® Group vs the LMA® Group. There was no severe adverse effect during the maneuver with both SGDs. No baby died, No.2 required endotracheal intubation for a second dose of SF as by protocol, and No. 1 was transferred to a higher level of care. Conclusion - Non-invasive SF administration via SGD has been done effectively at a second level Neonatal Unit and very early in the course of the disease therefore limiting transfer of the baby without complications with both SGDs. Improvement in gas exchange was more rapid in the iGel®Group. This result needs confirmation. In our experience iGel® was easier to use than LMA®.

Can we reduce worldwide neonatal mortality?

Worldwide neonatal mortality rate is still very high in many countries, with a sharp difference between developed and developing countries. The difference of interventions to be implemented for reducing neonatal mortality rate  in developing and developed countries will be discussed.

Sex-biased impact of endocrine disrupting chemicals on behavioral development and vulnerability to disease: Of mice and children.

Sex is a fundamental biological characteristic that influences many aspects of an organism's phenotype, including neurobiological functions and behavior as a result of species-specific evolutionary pressures. Sex differences have strong implications for vulnerability to disease and susceptibility to environmental perturbations. Endocrine disrupting chemicals (EDCs) have the potential to interfere with sex hormones functioning and influence development in a sex specific manner. Here we present an updated descriptive review of findings from animal models and human studies regarding the current evidence for altered sex-differences in behavioral development in response to early exposure to EDCs, with a focus on bisphenol A and phthalates. Overall, we show that animal and human studies have a good degree of consistency and that there is strong evidence demonstrating that EDCs exposure during critical periods of development affect sex differences in emotional and cognitive behaviors. Results are more heterogeneous when social, sexual and parental behaviors are considered. In order to pinpoint sex differences in environmentally-driven disease vulnerabilities, researchers need to consider sex-biased developmental effects of EDCs.

Proximate and ultimate causes of ritual behavior.

Ritual behaviour, intended as a specific, repetitive and rigid form of action flow, appears both in social and non-social environmental contexts, representing an ubiquitous phenomenon in animal life including human individuals and cultures. The purpose of this contribution is to investigate an evolutionary continuum in proximate and ultimate causes of ritual behavior. A phylogenetic homology in proximal mechanisms can be found, based on the repetition of genetically programmed and/or epigenetically acquired action patterns of behavior. As far as its adaptive significance, ethological comparative studies show that the tendency to ritualization is driven by the unpredictability of social or ecological environmental stimuli. In this perspective, rituals may have a "homeostatic" function over unpredictable environments, as further highlighted by psychopathological compulsions. In humans, a circular loop may have occurred among ritual practices and symbolic activity to deal with a novel culturally-mediated world. However, we suggest that the compulsion to action patterns repetition, typical of all rituals, has a genetically inborn motor foundation, thus precognitive and pre-symbolic. Rooted in such phylogenetically conserved motor structure (proximate causes), the evolution of cognitive and symbolic capacities have generated the complexity of human rituals, though maintaining the original adaptive function (ultimate causes) to cope with unpredictable environments.

Association of dopamine transporter and monoamine oxidase molecular polymorphisms with sudden infant death syndrome and stillbirth: new insights into the serotonin hypothesis.

Recent findings demonstrated the role of neurotransmitters in the aetiopathogenesis of sudden unexpected deaths in infancy. Although genes involved in serotonin metabolism have been proposed as risk factors for sudden infant death syndrome (SIDS), the contribution of additional neurotransmitters and genes different from the serotonin transporter (SLC6A4, 5-HTT) has not been investigated. Considering the common metabolic pathway and synergism between dopamine and serotonin, the role of dopamine transporter (SLC6A3, DAT) and monoamine oxidase A (MAOA) genes in SIDS and stillbirth (sudden intrauterine unexplained death, SIUD) was investigated. Genotypes and allelic frequencies of DAT and MAOA were determined in 20 SIDS and five stillbirth cases and compared with 150 controls. No association was found between DAT polymorphisms and SIDS either at genotype (P = 0.64) or allelic (P = 0.86) level; however, a highly significant association was found between MAOA genotypes (P = 0.047) and alleles (P = 0.002) regulating different expression patterns (3R/3R vs 3.5R/3.5R + 4R/4R) in SIDS + SIUD and controls. Analysis of combined 5-HTTLPR (serotonin transporter linked polymorphic region)/MAOA genotypes revealed that frequency of L/L-4R/4R genotype combination was eightfold higher in SIDS + SIUD than in controls (P < 0.001). Findings are discussed considering the metabolic association among DAT, 5-HTT and MAOA with special emphasis on the linked action of 5-HTT/MAOA in regulating serotonin metabolism of SIDS and SIUD infants.

Personality traits and endocrine response as possible asymmetry factors of agonistic outcome in karate athletes.

Individual variations of plasma levels of hormones testosterone (T) and cortisol (C), before (pre) and after (post) Kumite (real fight) and Kata (ritualized fight) were measured in male karate athletes and analyzed in relation with the agonistic outcome (i.e. winning or losing the fight) and personality trait measures. T and C increased only during Kumite contest and pre- and post-competition C levels were higher in losers than winners. Losers showed higher levels of harm avoidance and anxiety as well as lower level of novelty seeking than winners. Importantly, novelty seeking negatively correlates with pre C and the higher the level of risk assessment, emotionality and insecurity indexes the higher the pre C level. In conclusion, personality traits might be an important factor asymmetry between athletes influencing both the probability of winning or losing an agonistic interaction and the different anticipatory endocrine response to the incipient fight.

Genes regulating the serotonin metabolic pathway in the brain stem and their role in the etiopathogenesis of the sudden infant death syndrome.

Genotypes and allelic frequencies of TPH2, 5-HTTLPR, the 5-HTT (SLC6A4) intron 2 variable-number tandem repeat (VNTR) region, and the MAOA VNTR region were determined in brain-stem samples of 20 "genuine" SIDS cases and compared with results obtained from 150 healthy controls. The SNP G1463A responsible for 80% functionality loss of TPH2 (tryptophan hydroxylase 2) was not detected, neither in SIDS infants nor in the controls. In contrast, a strict relation was found between the 5-HTTLPR genotype and its allelic frequencies with SIDS cases. The L/L genotype and the long allele (L) of the promoter region of the serotonin transporter were significantly associated (likelihood ratio (LR) test, p<0.001) with the syndrome (L/L, 60% SIDS vs 14% controls; L, 80% SIDS vs 42.6% controls). Polymorphisms of the intron 2 VNTR of the same gene showed a trend for significant differences between genotypes 10/10 and 12/12 (LR test, p=0.068), with the L-12 haplotype being almost twofold in SIDS (44.5%) with respect to controls (23.4%). Differences were even higher considering the genotype combination L/L-12/12 (20% SIDS vs 2.6%), and variations among categories were statistically highly significant (p<0.001). Although additional differences were observed in the frequency of the MAOA (monoamine oxidase A) VNTR genotype 3R/3R between SIDS and controls (respectively 15% vs 26%), the results were not supported by statistical significance. Molecular polymorphisms are discussed considering their functional role in regulating serotonin synthesis (TPH2), neuronal reuptake (5-HTTLPR and 5-HTT intron 2), and catabolism (MAOA) in the nervous system of Italian SIDS infants. Comparisons are made with previous data obtained in different ethnic groups.