Uncertainty and anxiety: Evolution and neurobiology.

Anxiety is a complex phenomenon: Its eliciting stimuli and circumstances, component behaviors, and functional consequences are only slowly coming to be understood. Here, we examine defense systems from field studies; laboratory studies focusing on experimental analyses of behavior; and, the fear conditioning literature, with a focus on the role of uncertainty in promoting an anxiety pattern that involves high rates of stimulus generalization and resistance to extinction. Respectively, these different areas provide information on evolved elicitors of defense (field studies); outline a defense system focused on obtaining information about uncertain threat (ethoexperimental analyses); and, provide a simple, well-researched, easily measured paradigm for analysis of nonassociative stress-enhanced fear conditioning (the SEFL). Results suggest that all of these-each of which is responsive to uncertainty-play multiple and interactive roles in anxiety. Brain system findings for some relevant models are reviewed, with suggestions that further analyses of current models may be capable of providing a great deal of additional information about these complex interactions and their underlying biology.

Sex, defense, and risk assessment: Who could ask for anything more?

Over the 30 years since IBNS was founded, a central theme of "Translation" has emerged. This reflects increasing realization that mental disorders such as anxiety and depression are extremely widespread, expensive and painful to societies and individuals across the world. The Blanchard lab has been particularly involved in attempts to understand the evolutionary and functional mechanisms underlying defensive behaviors as a focal component of these disorders. This involved analysis of the relationships between threatening situations/stimuli, and the behaviors (flight, freezing, fight, and risk assessment) that respond to them, for rodents; and also attempts to link these relationships to human responsivity to similar threatening events: Linkages that are complicated by factors such as domestication and sex. In particular it is important to describe and characterize the organization of defensive patterns in people as well as nonhuman animals, and to understand how these patterns can become nonfunctional and pathological.

Are cognitive aspects of defense a core feature of anxiety and depression?

Anxiety and depression are highly prevalent behavior disorders, particularly in women. Recent preclinical work using animal models has been suboptimal in predicting the efficacy of drugs targeted at these conditions, suggesting a potential discrepancy between such models and the human disorders. Notably female animals tend to be equal to, or less responsive than, males in these tasks. A number of analyses suggest that mammalian defense patterns are complex: In addition to relatively discrete and immediate fight, flight, and freezing responses, a risk assessment pattern may occur in response to threat stimuli or situations with ambiguous elements. This pattern combines defensiveness with a number of cognition-linked behaviors such as sensory attention and orientation, approach, contact, and investigation of the potential threat. Studies measuring elements of this pattern suggest that female rats, and perhaps female mice, show higher levels than equivalent males. Higher female involvement may also occur in tasks involving learning/generalization/extinction of defensiveness to conditioned stimuli. Such findings are consonant with recent analyses of "female survival strategies" based on differential adaptiveness of cognitive components of defensiveness in females, due to the necessity of female care of offspring until they are independent. These data suggest the value of additional behavioral and functional analyses of cognitive aspects of defensive behavior; contributing to both an understanding of their underlying mechanisms, and providing more sensitive measures of drug responsivity for use with animal models.

Dissecting the brain's fear systems responding to snake threats.

We examined the behavioural responses and Fos expression pattern of rats that were exposed to snake threats from shed snakeskin and a live snake. We differentiated the behavioural responses and the pattern of Fos expression in response to the odour cues and mild threat from a live snake. Animals exposed to the snake odour alone or to the confined snake showed a great deal of risk assessment. Conversely, the intensification of odour during exposure to the live snake decreased the threat ambiguity, and the animals froze for a significantly longer period. Our Fos analysis showed that a pathway formed by the posteroventral part of the medial amygdalar nucleus to the central part of the ventromedial hypothalamic nucleus appeared to be solely responsive to odour cues. In addition, we showed increased Fos expression in a parallel circuit comprising the lateral amygdalar nucleus, ventral subiculum, lateral septum, and juxtadorsomedial region of the lateral hypothalamic area that is responsive to both the odour and mild threat from a live snake. This path is likely to process the environmental boundaries of the threat to be avoided. Both paths merge into the dorsal premammillary nucleus and periaqueductal grey sites, which all increase Fos expression in response to the snake threats and are likely to organize the defensive responses. Moreover, we found that the snake threat mobilized the Edinger-Westphal and supraoculomotor nuclei, which are involved in stress adaptation and attentional mechanisms.

Dissecting the brain’s fear systems responding to snake threats

We examined the behavioral responses and Fos expression pattern of rats that were exposed to snake threats from shed snakeskin and a live snake. We differentiated the behavioral responses and the pattern of Fos expression in response to the odor cues and mild threat from a live snake. Animals exposed to the snake odor alone or to the confined snake showed a great deal of risk assessment. Conversely, the intensification of odor during exposure to the live snake decreased the threat ambiguity, and the animals froze for a significantly longer period. Our Fos analysis showed that a pathway formed by the posteroventral part of the medial amygdalar nucleus to the central part of the ventromedial hypothalamic nucleus appeared to be solely responsive to odor cues. In addition, we showed increased Fos expression in a parallel circuit comprising the lateral amygdalar nucleus, ventral subiculum, lateral septum and juxtadorsomedial region of the lateral hypothalamic area that is responsive to both the odor and mild threat from a live snake. This path is likely to process the environmental boundaries of the threat to be avoided. Both paths merge into the dorsal premammillary nucleus and periaqueductal gray sites, which all increase Fos expression in response to the snake threats and are likely to organize the defensive responses. Moreover, we found that the snake threat mobilized the Edinger-Westphal and supraoculomotor nuclei, which are involved in stress adaptation and attentional mechanisms.

Repeated exposure of naïve and peripheral nerve-injured mice to a snake as an experimental model of post-traumatic stress disorder and its co-morbidity with neuropathic pain.

Confrontation of rodents by natural predators provides a number of advantages as a model for traumatic or stressful experience. Using this approach, one of the aims of this study was to investigate a model for the study of post-traumatic stress disorder (PTSD)-related behaviour in mice. Moreover, because PTSD can facilitate the establishment of chronic pain (CP), and in the same way, patients with CP have an increased tendency to develop PTSD when exposed to a traumatic event, our second aim was to analyse whether this comorbidity can be verified in the new paradigm. C57BL/6 male mice underwent chronic constriction injury of the sciatic nerve (CCI), a model of neuropathic CP, or not (sham groups) and were submitted to different threatening situations. Threatened mice exhibited enhanced defensive behaviours, as well as significantly enhanced risk assessment and escape behaviours during context reexposure. Previous snake exposure reduced open-arm time in the elevated plus-maze test, suggesting an increase in anxiety levels. Sham mice showed fear-induced antinociception immediately after a second exposure to the snake, but 1 week later, they exhibited allodynia, suggesting that multiple exposures to the snake led to increased nociceptive responses. Moreover, after reexposure to the aversive environment, allodynia was maintained. CCI alone produced intense allodynia, which was unaltered by exposure to either the snake stimuli or reexposure to the experimental context. Together, these results specifically parallel the behavioural symptoms of PTSD, suggesting that the snake/exuvia/reexposure procedure may constitute a useful animal model to study PTSD.

Defensive behaviors and brain regional activation changes in rats confronting a snake.

In the present study, we examined behavioral and brain regional activation changes of rats). To a nonmammalian predator, a wild rattler snake (Crotalus durissus terrificus). Accordingly, during snake threat, rat subjects showed a striking and highly significant behavioral response of freezing, stretch attend, and, especially, spatial avoidance of this threat. The brain regional activation patterns for these rats were in broad outline similar to those of rats encountering other predator threats, showing Fos activation of sites in the amygdala, hypothalamus, and periaqueductal gray matter. In the amygdala, only the lateral nucleus showed significant activation, although the medial nucleus, highly responsive to olfaction, also showed higher activation. Importantly, the hypothalamus, in particular, was somewhat different, with significant Fos increases in the anterior and central parts of the ventromedial hypothalamic nucleus (VMH), in contrast to patterns of enhanced Fos expression in the dorsomedial VMH to cat predators, and in the ventrolateral VMH to an attacking conspecific. In addition, the juxtodorsalmedial region of the lateral hypothalamus showed enhanced Fos activation, where inputs from the septo-hippocampal system may suggest the potential involvement of hippocampal boundary cells in the very strong spatial avoidance of the snake and the area it occupied. Notably, these two hypothalamic paths appear to merge into the dorsomedial part of the dorsal premammillary nucleus and dorsomedial and lateral parts of the periaqueductal gray, all of which present significant increases in Fos expression and are likely to be critical for the expression of defensive behaviors in responses to the snake threat.

Function evaluation of laryngeal reconstruction using infrahyoid muscle after partial laryngectomy in 37patients.

Treatment of small laryngeal cancerous lesions (T1 and T2) is based on partial endoscopic or open surgery and radiotherapy. In addition to the oncological imperative, these techniques must optimally preserve the functions of breathing, swallowing and phonation. OBJECTIVE: To analyze the above functions in patients treated with supracricoid laryngectomy and reconstruction using infrahyoid muscle. MATERIALS AND METHODS: Breathing, swallowing and phonation were analyzed in 37patients treated in two institutes between 2005 and 2015. All patients undergoing the above type of reconstruction with a minimum 1year's follow-up were included. Respiratory study noted any tracheotomy and measured peak inspiratory flow. Preservation of cricoarytenoid units and nasogastric intubation time, and DHI-30 self-administered questionnaire results were collected to analyze swallowing function. Phonation was assessed on the VHI-30 self-administered questionnaire. RESULTS: The rate of primary surgery without tracheotomy was 64.9% (13patients), with rapid resumption of oral feeding (mean intubation time, 13days). Mean VHI score was 28.3 and mean DHI 30score 2.7. Mean peak inspiratory flow was 203.3mL/min. CONCLUSION: Supracricoid laryngectomy with reconstruction using subhyoid muscle is an alternative technique for the treatment of small laryngeal cancerous lesions, providing uncomplicated functional outcome.

Epigenetic Delay in the Neurodevelopmental Trajectory of DNA Methylation States in Autism Spectrum Disorders.

Autism spectrum disorders (ASD) are hypothesized to originate in utero from perturbations in neural stem cell niche regions of the developing brain. Dynamic epigenetic processes including DNA methylation are integral to coordinating typical brain development. However, the extent and consequences of alterations to DNA methylation states in neural stem cell compartments in ASD are unknown. Here, we report significant DNA methylation defects in the subventricular zone of the lateral ventricles from postmortem brain of 17 autism diagnosed compared to 17 age- and gender-matched typically developing individuals. Both array- and sequencing-based genome-wide methylome analyses independently revealed that these alterations were preferentially targeted to intragenic and bivalently modified chromatin domains of genes predominately involved in neurodevelopment, which associated with aberrant precursor messenger RNA splicing events of ASD-relevant genes. Integrative analysis of our ASD and typically developing postmortem brain methylome datasets with that from fetal brain at different neurodevelopmental stages revealed that the methylation states of differentially methylated loci associated with ASD remarkably resemble the methylation states at earlier time points in fetal brain development. This observation was confirmed using additional methylome datasets from three other brain regions. Altogether, these findings implicate an epigenetic delay in the trajectory of normal DNA methylation states during the course of brain development that may consequently lead to deleterious transcriptomic events in ASD and support the hypothesis of an early developmental origin of ASD.

Spondylodiscitis after transoral robotic surgery: Retrospective 7-case series from the GETTEC group.

BACKGROUND: Cervical spondylodiscitis is a rare but severe complication of pharyngeal surgery. MATERIAL AND METHODS: This multicenter retrospective study reported all patients in the database of the French head and neck tumor study group (GETTEC) affected by cervical spondylodiscitis after transoral robotic surgery (TORS) for malignant pharyngeal tumor from January 2010 to January 2017. OBJECTIVES: To describe cases of post-TORS cervical spondylodiscitis, identify alarm signs, and determine optimal management of these potentially lethal complications. RESULTS: Seven patients from 6 centers were included. Carcinomas were located in the posterior pharyngeal wall. Tumor stage was T1 or T2. All patients had risk factors for spondylodiscitis. Mean time to diagnosis was 12.6days. The interval between surgery and spondylodiscitis diagnosis ranged from 20days to 4.5months, for a mean 2.1months. The most common symptom was neck pain (87%). Infections were polymicrobial; micro-organisms were isolated in 5 cases and managed by intravenous antibiotics, associated to medullary decompression surgery in 3 cases. Follow-up found favorable progression in 4 cases, and 3 deaths (mortality, 43%). CONCLUSION: This French multicenter study found elevated mortality in post-TORS spondylodiscitis, even in case of limited resection. Surgeons must be aware of this complication and alerted by persistent neck pain, fever, asthenia, impaired or delayed posterior pharyngeal wall wound healing or elevation of inflammatory markers. MRI is the most effective diagnostic radiological examination.

Risk assessment and serotonin: Animal models and human psychopathologies.

Risk assessment (RA) is an evolved, generally adaptive, mechanism comprising focused attention and appraisal of potential threat stimuli and situations. Initially characterized in animal models, it provides a number of behavioral and functional parallels to patterns of rumination, gaze biases, and other forms of affective cognition that appear to be disregulated in depression and anxiety. Serotonergic mechanisms are involved in these mood disorders, and an emerging body of evidence suggests that they may modulate the affective cognitive changes common to such psychopathologies. Findings of parallel effects of serotonin systems in RA would support a view that it may provide a useful behavioral endophenotype for translational research on mood disorders. This review examines the involvement of serotonergic mechanisms in both animal models of RA, and in an array of tasks focusing on affective cognitive changes in individuals with depression or anxiety. Results suggest substantial serotonin involvement in both RA behaviors measured in rats or mice, and in the "intersection of emotional and cognitive processes" [43] in people.

What we imagine is what we do? A critical overview about mental imagery as a strategy to study human defensive responses.

There is not a single and perfect instinctive behavior to react to threatening situations. However, the study of particular features of these situations suggests the existence of prototypical emotional reactions and associated defensive behaviors. Since all living beings are subjected to common evolutionary pressures, such as predation and conspecific competition, it is plausible that there is conservation of some basic defensive responses in their behavioral repertoire. The choice for approaching or withdrawing from a given situation depends, among others things, on environmental features, including the threat intensity and the distance from the source of the threat. If these basic responses were conserved in humans, they should be expressed in ways similar to those observed in non-human animals. Due to ethical reasons and easy application, mental imagery has been used to test this hypothesis. The studies included in this review point to the validity of this method, with both self-report and neurophysiological findings corroborating the hypothesis under scrutiny. Despite the need for additional investigation to deal with some limitations, the information obtained with this method can help to a better understanding of the conditions that provoke specific defensive behaviors and related emotions. This knowledge may also contribute to identify vulnerability factors for fear/anxiety-related disorders.

Assessment of swallowing function after circumferential pharyngolaryngectomy. A multicenter study by the GETTEC group.

OBJECTIVE: Circumferential pharyngolaryngectomy is performed for advanced pharyngeal tumor or in a context of postradiation recurrence. Several free or pedicle flaps have been described for pharyngeal defect reconstruction, with choice at the surgeon's discretion. The aim of this study was to evaluate long-term swallowing function according to the type of flap used for reconstruction. MATERIAL AND METHOD: A multicenter retrospective study was conducted from January to September 2016 within the French GETTEC head and neck tumor study group. All patients in remission after circumferential pharyngolaryngectomy were included and filled out the Deglutition Handicap Index (DHI) questionnaire and underwent swallowing function fiberoptic endoscopy assessment. 46 patients (39 men, 7 women) were included. Reconstruction used a tubularized forearm free flap (FFF group) in 19 cases, pectoralis major myocutaneous flap (PMMF group) in 15 cases and free jejunum flap (FJF group) in 12 cases. RESULTS: Mean DHI was 24: 20 in the FFF group, 23 in the FJF group and 25 in the PMMF group, without significant differences. 27 patients had normal swallowing, 9 mixed diet, 8 liquid diet and 3 were fed by gastrostomy. On endoscopy, free flaps (FJF and FFF) were associated with significantly greater rates of normal swallowing of saliva and yogurt than in the PMMF group (P=0.04). CONCLUSION: Type of flap reconstruction after circumferential pharyngolaryngectomy had no significant impact on postoperative swallowing function assessed on the self-administered DHI questionnaire.

Effects of estrus cycle stage on defensive behavior in female Long-Evans hooded rats.

This study investigated the influence of the estrus cycle in mediating cat odor-induced unconditioned and conditioned defensive behaviors in female Long-Evans hooded rats. Unconditioned defensive behaviors were assessed during predatory cue exposure; conditioned defensive behaviors were examined 24 h after threat exposure. Estrus phases were determined by microscopic examination of vaginal smears within 10 min of completing the behavioral tests. Compared to no-odor controls, female rats exposed to cat odor exhibited both unconditioned and conditioned defensive behaviors, including elevated levels of freezing, risk assessment and avoidance. Rats in proestrus and estrus exhibited reduced levels of defensive behavior during the unconditioned test trial compared to subjects in diestrus and metestrus. Specifically, estrus stages characterized by high levels of circulating estrogens and progesterone were associated with reduced immobility (i.e. freezing) and enhanced active defense (i.e. risk assessment), profiles that may enable mate seeking and subsequent reproduction in potentially dangerous or novel environments. These results suggest a specific role for ovarian hormone fluctuations in mediating unconditioned fear- and anxiety-like defensive behaviors during exposure to predatory odors.

Translating dynamic defense patterns from rodents to people.

Specific defensive behaviors of rodents are shaped by features of the eliciting threat stimuli and situation. Threat scenarios confirmed these relationships in people, with results substantially replicated in 4 additional scenario studies. Subsequent human studies involve computer games measuring fear as flight from threat stimuli and anxiety as alternation between two threats. Stabilometric studies have shown reduction in sway (freezing) to inescapable (e.g. with gun pointed at subject) threatening photographs; but enhanced lateral sway (flight attempts) to escapable threats; (gun pointed away from subject). Relationships between threat ambiguity, risk assessment, and anxiety have been validated by identification of videos of facial expressions to ambiguous threats, as anxiety; and systematic biases toward threat stimuli by anxious individuals. Enhanced rumination, interpretable as unsuccessful risk assessment, is a dynamic component of both anxiety and depression, particularly in women. While there is less experimental work on defensive threat/attack, a transdiagnostic "Fear of Harm" phenotype of aggression associated with fear suggests that this is a component of pathological as well as normal human defensive behavior.

The BTBR mouse model of idiopathic autism - Current view on mechanisms.

Autism spectrum disorder (ASD) is the most commonly diagnosed neurodevelopmental disorder, with current estimates of more than 1% of affected children across nations. The patients form a highly heterogeneous group with only the behavioral phenotype in common. The genetic heterogeneity is reflected in a plethora of animal models representing multiple mutations found in families of affected children. Despite many years of scientific effort, for the majority of cases the genetic cause remains elusive. It is therefore crucial to include well-validated models of idiopathic autism in studies searching for potential therapeutic agents. One of these models is the BTBR T+Itpr3tf/J mouse. The current review summarizes data gathered in recent research on potential molecular mechanisms responsible for the autism-like behavioral phenotype of this strain.

[Characteristics and management of ST-elevation myocardial infarction in France: Regional variations in 2010]. / Prise en charge du syndrome coronaire aigu avec sus-décalage de ST en France : variations régionales en 2010.

Data on regional variations in the characteristics, management and early outcome of patients admitted with ST-elevation myocardial infarction (STEMI) in France are limited. We used data from the FAST-MI 2010 registry to determine whether regional specificities existed, dividing the French territory into 6 larger geographical regions. Variations in the patients' characteristics were found, partly related to regional variations in demography. Acute reperfusion strategy showed more use of primary percutaneous coronary intervention in the greater Paris area, compared to other regions, which would be expected owing to geography and local availability of catheterization laboratories. Overall, however, in-hospital management showed more similarities than differences across regions. Complications, and in particular in-hospital mortality, did not differ significantly among regions.

Neuronal correlates of asocial behavior in a BTBR T (+) Itpr3(tf)/J mouse model of autism.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized, in part, by an inability to adequately respond to social cues. Patients diagnosed with ASD are often devoid of empathy and impaired in understanding other people's emotional perspective. The neuronal correlates of this impairment are not fully understood. Replicating such a behavioral phenotype in a mouse model of autism would allow us insight into the neuronal background of the problem. Here we tested BTBR T(+)Itpr3(tf)/J (BTBR) and c57BL/6J (B6) mice in two behavioral paradigms: the Transfer of Emotional Information test and the Social Proximity test. In both tests BTBR mice displayed asocial behavior. We analyzed c-Fos protein expression in several brain regions after each of these tests, and found that, unlike B6 mice, BTBR mice react to a stressed cagemate exposure in the Transfer of Emotional Information test with no increase of c-Fos expression in either the prefrontal cortex or the amygdala. However, after Social Proximity exposure we observed a strong increase in c-Fos expression in the CA3 field of the hippocampus and two hypothalamic regions of BTBR brains. This response was accompanied by a strong activation of periaqueductal regions related to defensiveness, which suggests that BTBR mice find unavoidable social interaction highly aversive.

Guidelines update: Post-treatment follow-up of adult head and neck squamous cell carcinoma: Screening for metastasis and metachronous esophageal and bronchial locations.

OBJECTIVE: The present article is an update of the guideline of the French Society of Otorhinolaryngology and Head and Neck Surgery (SFORL) on the post-treatment follow-up of adult head and neck squamous cell carcinoma concerning screening for metastasis and metachronous esophageal and bronchial locations. METHODS: A multidisciplinary work-group was entrusted with a review of the literature on the above topic. Guidelines were drawn up, based on the articles retrieved and the work-group members' own experience. These were then reviewed by an editorial group independent of the work-group. A coordination meeting then finalized the guidelines. Guidelines were graded A, B, C or "expert opinion" according to decreasing level of evidence.